CA2848263A1 - Novel disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated diseases - Google Patents

Abstract

The present invention relates to novel di-substituted diamino-3,4-cyclobutene-3-dione-1,2 compounds having the following general formula (I): on the pharmaceutical compositions containing these compounds and on the use of these compounds and compositions for the treatment of chemokine mediated pathologies.

Description

Novel di-substituted compounds of 3,4-diamino-cyclobutene-3-1,2-dione useful in the treatment of pathologies mediated by chemokines.
Field of the invention The present invention relates to novel di-substituted compounds of the diamino-3,4 cyclobutene-3-1,2-dione, on the pharmaceutical compositions containing these compounds as well that on the use of these compounds and these compositions for the pathology treatment mediated by chemokines.
State of the art prior to the invention:
Chemokines or cytokines are small, soluble proteins. Their role best known is the attraction and control of the activation state of the system cells immune. All the chemokines perform their functions by binding to coupled receptors to G proteins.
Some chemokines are considered pro-inflammatory. Secretion of these chemokines can be induced during the immune response to promote the arrival of cells of the immune system at an infectious site.
There are two types of chemokines: pro-inflammatory chemokines and chemokines constituent.
Proinflammatory (or inducible) chemokines are produced at level of sites of inflammation by infiltrated tissue cells or leukocytes, after contact with a pathogen.
Constituent (or homeostatic) chemokines are produced in organs lymphoid and in some non-lymphoid organs such as skin and mucous membranes. They regulate lymphocyte trafficking and the localization of lymphocytes within these bodies during lymphopoiesis but also to maintain immunosurveillance.
The nomenclature of these chemokine receptors is based on the group of chemokines to which his ligand belongs. Thus, the receivers corresponding to chemokines of the group CXC are, for example, called CXCR1, CXCR2, CXCR3, CXCR4, etc., and the receptors corresponding to the chemokines of the group CC are, for example, called CCR1, CCR3, etc. These receptors all have a similar tertiary structure, and they are coupled WO 2013/061004

2 to a G protein: they are therefore part of the GPCR superfamily (G Protein Coupled Receptor).
Interleukin-8 or IL-8 (also named CXCL-8) is a member of the family of the chemokines CXC, which plays a vital role in the recruitment of neutrophils to the site of inflammation. Two receptors, CXCR1 and CXCR2 are known to be specifically activated by IL-8. While CXCR2 binds with a strong affinity to IL-8 and related chemokines such as CXCL6, CXCL5, CXCL3, CXCL2 and CXCL1, CXCR1 is only binds to IL-8. High levels of IL-8 and related chemokines (CXCL5, CXCL2 & CXCL1) have been described in inflammatory acne lesions (J Invest Dermatol.
2006; 126: 1071-9; Am J Pathol. 2005; 166 (6): 1691-9; Diagn Pathol. 2007 Jan 30; 2: 4).
First clues demonstrate the expression of CXCR2 in acne inflammatory (Trivedi et al. J Invest Dermatol. 2006 126 (5): 1071-9). Thus, antagonists duplicates of CXCR1 and CXCR2 could rapidly reduce the deleterious effects of reply inflammatory by IL-8.
Patent application WO 02/083624 (SCHERING / PHARMACOPEIA) discloses more particularly substituted 1,2-cyclobutenedione compounds to modulate chemokine receptor activity of CXC type, and more particularly the activity of CXCR1 and CXCR2 receivers. Among these compounds, the compound SCH-527123 (corresponding to example 360.71 on page 281), also called Navarixin, is being development (Phase II) for the treatment of pulmonary disease chronic obstructive (or COPD for Chronic Obstructive Pulmonary Disease). This compound also made the subject of phase II studies in asthma and psoriasis, but these developments have been arrested.
It is now known that many pathologies of inflammatory order are mediated by chemokines. However, there is an unmet need to date treat the inflammatory component of pathologies of interest in the field of dermatology as for example acne, rosacea or neutrophilic dermatoses, especially psoriasis.
In the same way, the promise to obtain new effective therapies to treat chemokine-mediated diseases using receptor antagonists to chemokines was not held. Indeed, several clinical studies have failed in phase II. One of the reasons can explain these failures is the overlap of the biological effects of different WO 2013/061004

3 chemokines induced in a pathological situation. To this day, the traditional Drug discovery process aims to identify molecules targeting a specific receiver no effect off target. This approach is probably not the most suitable to treat complex inflammatory diseases. More and more approaches seem favor the search for antagonistic molecules with broad spectrum of action (promiscuous compounds), said approaches may thus be more effective in treating complex diseases and Multifactorial (Frantz S. Drug discovery: playing dirty.
13; 437 (7061): 942-3; Roth BL, DJ Sheffler, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia.
Nat Rev Drug Discov. 2004 Apr; 3 (4): 353-9.) However, the applicant has discovered new compounds having an activity antagonist not only vis-à-vis receivers CXCR1 and CXCR2, but also a strong antagonist activity with respect to chemokine receptors, including CCR6 receivers and CXCR3. These new compounds surprisingly polypharmacology, which gives them an additional interest compared to to compounds already known in the treatment of pathologies mediated by chemokines, and more particularly dermatological pathologies.
In addition, these new compounds have good liver stability lower than already described compounds capable of blocking the activation of CXCR1 receptors and as for example the compound SCH-527123. This particular property presents the advantage to have new compounds having, surprisingly, a more adapted for topical treatment of dermatological conditions. In indeed, their instability liver function leads to low or no systemic exposure and therefore effects limited secondary Another particularity of the compounds described in the present invention is their constant of dissociation with respect to the CXCR1 and CXCR2 receptors, a constant which is good less than that of the compounds described in the patent application WO
02/083624, as by example the SCH-527123. Indeed, the molecule SCH-527123 has been described for have a time dissociation of the order of 22h (pseudo-irreversible dissociation) (Pharmacological Characterization of SCH-527123, a Potent Allosteric CXCR1 / CXCR2 Antagonist.
JPET
322: 477-485, 2007), whereas the dissociation times of the compounds of the present invention are much lower.

WO 2013/061004

4 Examples from the literature show that rapid dissociation of antagonists favors a decrease in their toxicity. This has been described for antagonists of receptors dopamine D2 (Am J Psychiatry (2001) 158 (3): 360-369), N-methyl-D-receptors aspartate (NMDA) (Nat Rev Drug Disc (2006) 5 (2): 160-170.) As well as for anti-inflammatory Non-steroidal drugs (Lett Drug Des Discov (2006) 3 (8): 569-574 and Pharm Med (2008) 22 (1): 23-34). Indeed, a long dissociation time would rather tend to induce effects undesirable. With fast dissociation times, the compounds according to the invention therefore, reduced side effects.
Summary of the invention A first object according to the invention relates to new di-substituted compounds of the 3,4-diamino-cyclobutene-3-1,2-dione having the general formula (I) next:

R4, X

(I) as well as their pharmaceutically acceptable salts, solvates or hydrates for which substituents R1, R2, R3 and R4 are as defined hereinafter in the detailed description of the invention.
A second object according to the invention relates to a pharmaceutical composition including a an effective amount of a compound of the general formula (I) of one of its salts or one of its pharmaceutically acceptable solvates or hydrates in combination with a solvent or a pharmaceutically acceptable carrier.
A third object according to the invention concerns a compound or a composition as described above for its use as a drug.

WO 2013/061004

5 A fourth object according to the invention relates to a compound or a composition as described above for its use in the disease treatment mediated by chemokines.
A fifth object according to the invention concerns a compound or composition pharmaceutical as described above for its use in the treatment of diseases of the group including neutrophilic dermatoses, including psoriasis, dermatitis atopic, acne, rosacea, asthma, obstructive lung disease chronicles, respiratory diseases of adults, arthritis, intestinal diseases inflammatory Crohn's disease, transplant rejection, cystic fibrosis and skin cancer.
Detailed description of the invention Unless otherwise indicated, the following definitions apply to all the description and claims.
These definitions apply regardless of whether a term is used alone or combination with other terms. For example, the definition of the term aryl applies both to aryl as such and to the aryl part of aryloxy term.
"Alkyl" denotes a linear or branched saturated hydrocarbon chain whose number of carbon atoms is specified.
When the number of carbon atoms is not specified, it means that the alkyl chain contains from 1 to 20 carbon atoms.
Preferred alkyl radicals contain from 1 to 12 carbon atoms, and those even more preferred contain from 1 to 6 carbon atoms in the chain.
Alkoxy "denotes an oxygen substituted by an alkyl radical as defined previously.
Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
Aryl means a monocyclic or polycyclic aromatic ring system (2 to 3 rings) comprising from 6 to 14 carbon atoms, and preferably from 6 to 10 atoms of WO 2013/061004

6 carbon.
By way of examples of aryl radicals, mention may be made of phenyl radicals, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl and fluorenyl.
Heteroaryl refers to a monocyclic or polycyclic aromatic system (2 to 3 cycles) comprising from 5 to 14 ring atoms, preferably from 5 to 10 atoms cyclic, in which one or more of the atomic atoms represents (s) one or more (from I to 5) heteroatom (s) selected from the group consisting of nitrogen, oxygen and sulfur The preferred heteroaryls contain 5 or 6 ring atoms and I to 3 heteroatoms.
The prefix aza, oxa or thia before the name of the heteroaryl root means that at least one nitrogen, oxygen or sulfur is present in the cycle, respectively.
A nitrogen atom of a heteroaryl may be optionally oxidized to N-oxide.

As suitable heteroaryl examples, mention may be made of heteroaryls following pyridyl, pyrazinyl, furany [e, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazoly thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyk4 triazolyl, 1,2,4-thiadiazo1y1e, pyrazinyl, pyridazinyl, quinoxalinyl, phta [azinyie, imidazo [1,2-a]
pyridiny e, imidazo [2.1-1: 3] thia.zolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinofin.yle, imidazolyl, -thienopyridyl, quinazolinyl, -thienopyrimid.yl, pyTrolopyridyle, imidazopyridyl, isoquinolinyl, benzazaindolyl, 1,2,4-triazinyl and benzothiazolyl.
Arylalkyl denotes a radical whose aryl and alkyl parts are such as defined above above.
By way of examples of arylalkyl, mention may be made of benzyl radicals, phenethyl and naphthalènylmethyle.
The link to the structure to which it is attached is by the radical alkyl.
<ffletéroaryialkyle denotes a radical whose heteroaryl and alkyl are such that defined above.
By way of examples of heteroarylalkyl, mention may be made of radicals pyridylmethyl, pyridyk.4.by le, Diazolylmethyl, imidazolylethyl, pyrazolyimethyl. and pyrazolyléthyle ..
The link to the structure to which it is attached is by the radical alk, _: μ, 71st Cycloalkyl means a non-aromatic hydrocarbon ring system having from 3 to 10 carbon atoms, preferably from 5 to 10 carbon atoms, and from one to three cycles.

WO 2013/061004

7 The preferred cycloalkyl radicals contain from 5 to 7 ring atoms.
As free from cycloalkyl radicals, mention may be made of the radicals cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl.
Cycloalkylalkyl "denotes a radical whose cycloalkyl and alkyl moieties are such that defined above.
Examples of cyalkalkylalkyl include radicals cyclopropylméth_yle, cyclopropyethyl, cyc to'buty fru ethyl, cyc tobuty such as hyle, cyc topen tylméthy te, cyc lop entylethyl, CyC Io hexylmethyl, cyclohexylethyl, norbornylmethyl and adamantyiméthyte.
The link to the structure to which it is attached is made by the radical alkyl.
Heterocycloalkyl means a non-aromatic hydrocarbon ring system, having 4 to 10 carbon atoms, preferably 5 to 10 carbon atoms, and deun to three cycles and comprising from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
Preferred heterocycloalkyl radicals contain from 5 to 7 atoms cyclical.
As examples of heterocycloalkyl radicals, mention may be made of radicals tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl and 7-oxa bicyclo [2.2.1] -heptanyl.
Fluorinated alkyl means an alkyl radical as defined previously substituted by one or several fluorine atoms.
As examples of fluorinated alkyl radicals, mention may be made of radicals fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.
Perfluorinated alkyl means an alkyl radical as defined above in which each hydrogen atom has been substituted by a fluorine atom.
As examples of perfluorinated radicals, mention may be made of radicals trifluoromethyl, and pentafluoroethyl.

WO 2013/061004

8 Thus, a first object according to the invention relates to novel compounds di-substituted for the 3,4-diamino-cyclobutene-3-1,2-dione having the general formula (I) next or one of its pharmaceutically acceptable salts or solvates:

R4, X

(I) R1 represents a hydrogen atom or a methyl, R2 represents a five-membered ring selected from structures (1), (2), (3) and (4) following:
xiNt7a / 7a X X ' R5 P (R5 1 R5 ___________________________ X R5), X
(1) (2) (3) (4) in which R5, R7a, X and X 'have the meaning given below, R3 represents an aromatic or heteroaromatic ring selected in the group formed by the cycles corresponding to the following formulas (a) to (o):

WO 2013/061004

9 I +
= R7 N
YY
/ 1 ¨R7 0/1 ¨R7 / __ \ I / R7 4 _ii_N R7 0-- z R7aR7 a (a B C D E) gli Y el Y = Y lel Y
(f) (g) (h) (I) _R7 N
NOT
NN / 1 I __ R7 / 1 R7 ; _______ i (NN N
NOT

(i) (k) (I) (m) 001 iel NN
(n) (0) in which R7, R7a, Y and Z have the meaning given below, being specified that cycles (a) to (o) may possibly carry more than one R7 group, identical or different, the total number of such groups R7 being at most equal to the number of atoms substitutable cycle;
R4 represents an aromatic or heteroaromatic ring selected in the group formed by the cycles corresponding to the following formulas (p) to (z) and (aa) to (ak):

WO 2013/061004

10 R10 Es R12 R10 R12 R10 R12 R10 R12 NNN \ R14 el \\ \
NN. NOT
r.
. nn H
R13 H R13 H.
H
(p) (a) (r) (s) II
R10 R12 R10NC) R10NN R10 (t) (u) (y) (w) N, - N R10 N R12 I
,OR
1 1 I II N1) \ __ ( I
OH OH OH
(x) (Y) (z) (aa) I
R15r \ iv R13 N SI ---- I R10,) 7S R15, N
N r ) ¨

(ab) (ac) (ad) (ae) (af) R10 \ R12 R10R12 R12 R1 5, .N., .. õ ...-- .., /
R9 R1 5, .. N., .... õ.õ ..-- ,, NOT/

(ag) (ah) (ai) (aj) (ak) in which R7, R8, R9, R10, R11, R12, R13, R14 and R15 have the meaning given above after, R5 represents a hydrogen atom, a fluorine atom, an alkyl radical having from 1 to 5 carbon atoms or a fluorinated or perfluorinated alkyl radical having from 1 to 5 atoms of carbons, WO 2013/061004

11 R6 represents a hydrogen atom, a -COOtBu radical or a -COOBn radical, R7 represents a halogen, a radical -R16, -CF3, -COR16, -OR16, -NR16R17, -NO2, -CN, -S02R16, -SO2NR16R17, -NR16COR17, -CONR16R17, -NR16CO2R17 or -OO2R16, R7a represents a hydrogen atom or an alkyl radical having from 1 to 5 atoms of carbons, R8 represents a hydrogen atom, a halogen atom, a radical -OH, a radical -SH, -CONHOR16, -CONR160H, -NR16R17, -SO3H, -000R16, -NHSO2R16, -SO2NR16R17, -NHCOR16, -CONR16R17, -NR16CO2R17, -NHSO2NR16R17, -OO2R16, pyrrolyl, imidazolyl, triazolyl or tetrazolyl, R9, R10, R11 and R12 are the same or different and are independently chosen in the group consisting of hydrogen, a halogen atom, an alkyl radical, alkoxy, -CF3, -OCF3, -OH, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -CO2R16, or even when two of the radicals R9, R10, R11 and R12 are in ortho position on an aromatic or heteroaromatic ring selected from the group constituted by the cycles of formulas (p) to (z) and (aa) to (ak) above, then they can form together, with the bond that unites them, an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, R13 and R14 are the same or different and are independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl radical, CF3, -OCF3, -OH, -SH, -CN, -SO2R16, -SO2NR16R17, -NHSO2NR16R17, -NR16R17, -NR16CONR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -CO2R16, R15 represents a hydrogen atom, a radical -OH, -SO2R16, -COR16, -CO2R16, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R16 and R17 are the same or different and are independently selected from the group consisting of a hydrogen atom, an aryl radical, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, fluoroalkyl having 1 to 5 carbon atoms, cycloalkyl or cycloalkylalkyl, a WO 2013/061004

12 CH2COOR18 group in which R18 represents an alkyl radical having from 1 to 5 atoms of carbon, or else when R16 and R17 are borne by the same nitrogen atom they form a heterocycle having between 3 and 7 links and possibly comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen in addition to the atom nitrogen by which they are carried, said heterocycle may be substituted by a group alkyl having 1 to 5 carbon atoms or a group ¨COOR18 in which R 18 represent an alkyl radical having 1 to 5 carbon atoms ;.
X and X ', identical or different, represent an oxygen atom, an atom of sulfur, or nitrogen atom substituted with an R 6 radical, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R15, and Z represents a carbon or nitrogen atom In a preferred embodiment according to the invention, the compounds thus that their salts, pharmaceutically acceptable solvates or hydrates, have the formula general (I) in which:
R1 represents a hydrogen atom, R2 represents a five-membered ring selected from structures (1), (2) and (3) following:
x.vR7a X
R5 P (R5 1 R5) __________________________ X R7a (1) (2) (3) in which R5, R7a, X and X 'have the meaning given below, R3 represents an aromatic or heteroaromatic ring selected in the group formed by the cycles of the following formulas (a), (b) and (d):

WO 2013/061004

13 . R7 / 1 ¨R7 0 / __ \\ Ij R7 0-- z 7a (a) (b) R7a (d) in which R7, R7a, Y and Z have the meaning given below, being specified that cycles (a), (b) and (d) may optionally carry more than one R7 group, identical or different, the total number of such groups R7 being at most equal to the number atoms substitutable for the cycle;
R4 represents an aromatic or heteroaromatic ring selected in the group formed by the cycles corresponding to the formulas (p), (q), (t), (z), (ad), (ag) and (ah) following:

Ri :, R12 R10 R12 R11 R

I
NNN
\\ R9 el \ H R13 H

(P) (a) (t) (z) R10 \ R12 Ri OR12 ¨ R15, õ.N., ....... õ, --- .. ,, s /

(Ad) (ag) (ah) in which R8, R9, R10, R11, R12, R13 and R15 have the meaning given below, R5 represents a hydrogen atom, a fluorine atom, an alkyl radical having from 1 to 5 carbon atoms or a fluorinated or perfluorinated alkyl radical having from 1 to 5 atoms of carbons, R6 represents a hydrogen atom, a COOtBu radical or a COOBn radical, WO 2013/061004

14 R7 is halogen, R16, -CF3, -COR16, -OR16, -NR16R17, -NO2, -CN, -S02R16, -SO2NR16R17, -NR16COR17, -CONR16R17, -NR16CO2R17 or -OO2R16, R7a represents a hydrogen or an alkyl radical having from 1 to 5 carbon atoms carbons, R8 represents a hydrogen atom, a radical -OH, -SH, -CONHOR16, -CONR160H, -NR16R17, -SO3H, -000R16, -NHSO2R16, -SO2NR16R17, -NHCOR16, -CONR16R17, -NR16CO2R17, -NHSO2NR16R17, -OO2R16, pyrrolyl, imidazolyl, triazolyl or tetrazolyl, R9, R10, R11 and R12 are the same or different and are independently chosen in the group consisting of a hydrogen atom, a halogen atom, a radical alkyl, alkoxy, -CF3, -OCF3, -OH, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -OO2R16, or even when two of the radicals R9, R10, R11 and R12 are in ortho position on an aromatic or heteroaromatic ring selected from the group constituted by the cycles corresponding to formulas (p), (q), (t), (z), (ad), (ag) and (ah) above, so they can to form together, with the bond which unites them, an aryl, heteroaryl ring, cycloalkyl or heterocycloalkyl, R13 is selected from the group consisting of a hydrogen atom, an atom halogen, a alkyl radical, -CF3, -OCF3, -OH, -SH, -CN, -SO2R16, -SO2NR16R17, -NHSO2NR16R17, -NR16R17, -NR16CONR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -CO2R16, R15 represents a hydrogen atom, a radical -OH, -SO2R16, -COR16, -OO2R16, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R16 and R17 are the same or different and are independently selected from the group consisting of a hydrogen atom, an aryl radical, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, fluoroalkyl having 1 to 5 carbon atoms, cycloalkyl or cycloalkylalkyl, a -CH2COOR18 group in which R18 represents an alkyl radical having from 1 to 5 atoms of carbon, WO 2013/061004

15 or else when R16 and R17 are borne by the same nitrogen atom they form a heterocycle having between 3 and 7 links and possibly comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen in addition to the atom nitrogen by which they are carried, said heterocycle may be substituted by a group alkyl having 1 to 5 carbon atoms or a group ¨COOR18 in which R 18 represent an alkyl radical having 1 to 5 carbon atoms ;.
X and X ', identical or different, represent an oxygen atom, an atom of sulfur, or nitrogen atom substituted with an R 6 radical, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R15, and Z represents a carbon or nitrogen atom.
In a more particularly preferred embodiment according to the invention, compounds as well as their pharmaceutically acceptable salts, solvates or hydrates, answer the formula (I) above wherein:
R1 represents a hydrogen atom, R2 represents a ring with five atoms of structure (1) following:
R5 P ( (1) in which R5 and X have the meaning given below, R3 represents a heteroaromatic ring corresponding to the following formula (d):

WO 2013/061004

16 Y
/ ____ \\ Ij R7 z (D) in which R7, Y and Z have the meaning given below, being specified that cycle (d) can possibly carry several R7 groups, identical or different, the total number of such R7 group being at most equal to the number of ring substitutable atoms ;
R4 represents an aromatic ring corresponding to the following formula (t):

R9 el (T) in which R8, R9, R10, R11 and R12 have the meaning given below, R5 represents a hydrogen atom, a fluorine atom, an alkyl radical having from 1 to 5 carbon atoms or a fluorinated or perfluorinated alkyl radical having from 1 to 5 atoms of carbons, R6 represents a hydrogen atom, a COOtBu radical or a COOBn radical, R7 represents a halogen atom, a radical R16, -CF3, -COR16, -OR16, -NR16R17, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -CONR16R17, -NR16CO2R17 or -CO2R16, R8 represents a hydrogen atom, a radical -OH, -SH, -CONHOR16, -CONR160H, -NR16R17, -SO3H, -000R16, -NHSO2R16, -SO2NR16R17, -NHCOR16, -CONR16R17, -NR16CO2R17, -NHSO2NR16R17, -OO2R16, pyrrolyl, imidazolyl, triazolyl or tetrazolyl, R9, R10, R11 and R12 are the same or different and are independently chosen in the group consisting of a hydrogen atom, a halogen atom, a radical alkyl, alkoxy, -WO 2013/061004

17 CF3, -OCF3, -OH, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -OO2R16, or even when two of the radicals R9, R10, R11 and R12 are in ortho position on the aromatic ring (t), they can form together, with the binding that brings them together, one aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring, R15 represents a hydrogen atom, a radical -OH, -SO2R16, -COR16, -OO2R16, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R16 and R17 are the same or different and are independently selected from the group consisting of a hydrogen atom, an aryl radical, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, fluoroalkyl having 1 to 5 carbon atoms, cycloalkyl or cycloalkylalkyl, a CH2COOR18 group in which R18 represents an alkyl radical having from 1 to 5 atoms of carbon, or else when R16 and R17 are borne by the same nitrogen atom they form a heterocycle having between 3 and 7 links and possibly comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen in addition to the atom nitrogen by which they are carried, said heterocycle may be substituted by a group alkyl having 1 to 5 carbon atoms or a group ¨COOR18 in which R 18 represent an alkyl radical having 1 to 5 carbon atoms ;.
X represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R6, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R15, and Z represents a carbon atom or a nitrogen atom.

WO 2013/061004

18 Among the more particularly preferred compounds, mention may be made, for example those chosen in the list including:

2-hydroxy-N, N-dimethyl-3 - (2- {[(5-methyl-furan-2-yl) - (2-methyl-tetrahydro) furan-2-y1) -methyl] -amino} -3,4-dioxoocyclo-butyl-1-enylamino) -benzamide 2-hydroxy-N, N-dimethyl-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-y1) -methyl] -amino} -3,4-dioxo-cyclohexyl-1-enylamino) -benzamide (S) -1- [2-fluoro -3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2 y1) -methyl] -amino} -3,4-dioxo-cyclohexyl-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate methyl 4 / - (5) -1- [2-fluoro-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophenyl)}
2-yl) -methyl] -amino} -3,4-dioxo-cyclobutyl-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate isopropyl (5) -1- [2-fluoro-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-y1) -methyl] -amino} -3,4-dioxo-cyclo-butyl-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate ethyl (R) -1- [2-hydroxy-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-y1) -methyl] -amino} -3,4-dioxo-cyclo-but-1-enylamino) -benzoyl] -pyrrolidine-2-methyl carboxylate (5) -1- [2-hydroxy-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-y1) -methyl] -amino-3,4-dioxo-cyclo-but-1-enylamino) -benzoyl] -pyrrolidine-2-methyl carboxylate 2-hydroxy-N-methyl-3- (2 - {[(S) - (5-methyl-furan-2-yl) -tetrahydro-thiophenyl) 2-methyl-methyl]
amino} -3,4-dioxo-cyclo-but-1-enylamino) -N- (2,2,2-trifluoro-ethyl) -b enzamide 9 / - {[2-hydroxy-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl)}
methyl] -amino} -3, 4-dioxo-cyclo-butyl-1-enylamino) -benzoyl] -methyl-amino-methylacetate 10β-Chloro-2-hydroxy-N, N-dimethyl-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-Y1) -methyl] -amino} -3,4-dioxo-cyclo-but-1-enylamino) -benzene sulfonamide 2-hydroxy-N, N-dimethyl-3 - (2 - {[(R) - (5-methyl-furan-2-yl) -tetrahydro]
furan-2-yl-methyl] -amino} -3,4-dioxo-cyclo-but-1-enylamino) -benzamide 2-hydroxy-N, N-dimethyl-3 - (2 - {[(S) - (5-methyl-furan-2-yl) -tetrahydro]
furan-2-yl-methyl] -amino} -3,4-dioxo-cyclo-but-1-enylamino) -benzamide 15 / (5) -1 - [2-Fluoro-3 - (2 - {[(5-methylfuran-2-yl) - (tetrahydro)}
thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobutyl-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate methyl 18 / (+ 2-hydroxy-N-methyl-3- (2 - {[(S) - (5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-y1) -methyl-amino-3,4-dioxo-cyclo-but-1-enylamino) -N- (2,2,2-trifluoro-ethyl) -b enzamide

19 /
(-) - {[2-hydroxy-3 - (2 - {[(S) - (5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-y1) -methyl] -amino-3,4-dioxo-cyclo-butyl-1-enylamino) -benzoyl] -methyl-amino-acetate methyl

20 /
(-) - 1- [2-hydroxy-3 - (2- {R (S) -5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-) y1) -methyl] -amino-3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2- (R) -methyl carboxylate

21 /
(+ 6-chloro-2-hydroxy-N, N-dimethyl-3 - (2 - {[((S) -5-methyl-furan-2-yl) -(Tetrahydro -thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclo-butyl-1-enylamino) -benzamide

22 / (-) - 3 - [4-chloro-2-hydroxy-3 - (4-methyl-piperazin-1-sulfonyl) -phenylamino] -4- {[(5 -methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -cyclo but-3 -ene-1,2-dione A second object according to the invention relates to a pharmaceutical composition including a effective amount of a compound of general formula (I) or a salt pharmaceutically acceptable amount of said compound as described above in association with a solvent or a pharmaceutically acceptable carrier.
A third object according to the invention concerns compounds corresponding to the general formula (I), and their pharmaceutically acceptable salts, solvates or hydrates or a pharmaceutical composition comprising an effective amount of a compound responding to the general formula (I), a salt thereof or a solvate or hydrate thereof pharmaceutically acceptable for use as a medicine.
A fourth object according to the invention concerns compounds corresponding to the general formula (I), and their pharmaceutically acceptable salts, solvates or hydrates or a pharmaceutical composition comprising an effective amount of a compound responding to the general formula (I), a salt thereof or a solvate or hydrate thereof pharmaceutically acceptable for their use in the treatment of diseases mediated by cc-chemokines.
A fifth object according to the invention relates to a method for treating diseases mediated by α-chemokines using a compound of the formula general (I) that its pharmaceutically acceptable salts, solvates or hydrates or a pharmaceutical composition comprising an effective amount of a compound responding to the general formula (I), a salt thereof or a solvate or hydrate thereof pharmaceutically acceptable.
Examples of c-chemokine mediated diseases include dermatoses neutrophils, including psoriasis, atopic dermatitis, acne, rosacea, asthma, chronic obstructive pulmonary diseases, respiratory diseases adults, arthritis, inflammatory bowel diseases, Crohn's disease, rejection of transplant, the cystic fibrosis and skin cancers.
By neutrophilic dermatoses, in its broadest sense, the term Sweet's syndrome, eccrines hydranite >>, SAPHO syndrome, Sneddon Wilkinson syndrome, the pyoderina gangrenosum, erythema elevatum duitinum, psoriasis, [e psoriasis vulgaris, the pustular psoriasis, palmoplantar pustulosis, exanthematous pustulosis (PEAG), the.
pustulosis, vasculitis, acro-pusttdosis of children, Behcet's disease, as well as some oily diseases such as herpes derived as dermatitis, the dermatosis neutrophilic IgA, lgA intra-epidermis pustilosis, bullous pernphigoid, the pemphigus to IgA, vasculitis, Leroy Reiter syndrome Fiellingeraa pustulose scalp, continuous acrodermatitis of flallopeau and dermatoses related to angio-irnni imob I polish lymphodenopathy, with dysmelopoesis induced by cyclophospha-p-.ANCA.
antibody.
In a preferred embodiment according to the invention, the compound or composition aforementioned pharmaceutical is used in the treatment of diseases dermatological neutrophilic dermatoses, especially psoriasis, dermatitis atopic, acne and Rosacea.
Another aspect of the invention relates to the use of a compound corresponding to the formula (I), and their pharmaceutically acceptable salts, solvates or hydrates acceptable or still the use of a pharmaceutical composition comprising a quantity effective one compound of general formula (I), a salt thereof or a solvates or pharmaceutically acceptable hydrates for the preparation of a medicament for the treatment of diseases of the group comprising neutrophilic dermatoses, especially the psoriasis, atopic dermatitis, acne, rosacea, asthma, lung diseases chronic obstructive diseases, adult respiratory diseases, arthritis, diseases inflammatory bowel diseases, Crohn's disease and skin cancers.

The compounds of general formula (I) of the present invention are prepared following one or several of the synthetic routes as described below or that they emerge various examples of preparation given below without limitation.
The general synthetic route for the preparation of the compounds of formula (III) is illustrated Figure 1. Sequential processing of alkylated squarate intermediates (A) with the amines R'2-NH2 and R'3-NH2 gives the compounds of formula (III). In the formula (A), R'l is a C1-C6 alkyl, preferably methyl or ethyl. The reaction is performed in a inert and polar solvent (or in a mixture of solvents) such as ethanol, methanol, the dimethylsulfoxide, dimethylformamide or acetonitrile. Amines R'2-NH2 and R'3-NH2 can be used as free bases or in the form of salts. The reactions can be conducted in the presence of a suitable base such as triethylamine, diisopropylethylamine, sodium carbonate or potassium carbonate and at 25 C or preferably at elevated temperatures of 50-80 C. The reaction time is usually between 1 hour and 72 hours to have a complete conversion.
The amines R'3-NH2 of formula (IX) are prepared according to scheme 2 from of reagents using methods well known to those skilled in the art described in organic synthesis textbooks such as Comprehensive Organic Functional Group Transformation Vol. 1-7 ARKatritzky, O. Meth-Cohn, CWRees, Pergamon Press 1998.
The primary alcohols (IV) [in which X and R have the same meaning as X and R5 respectively above for the compounds of the general formula (I) are oxidized aldehydes of formula (V) under Swern conditions (Mancuso, AJ, Huang, S. L .; Swern D. (1978). "Oxidation of long-chain and related alcohols to carbonyls by dimethyl sulfoxide "activated" by oxalyl chloride "J. Org Chem 43 (12), 2480-2482) or with pyridinium chlorochromate.
The aldehyde of formula (V) is successively treated with a reagent of Grignard aryl or heteroaryl or with a lithiated derivative to give a secondary alcohol of formula (VI). The corresponding azides (VII) are prepared from the alcohols (VI) or transforming them mesylates (VIII) which are then treated with the metal azides (eg azide of sodium), or by transforming them directly into azide after treatment with the azide of diphenylphosphoryl (DPPA). The azide (VII) is finally reduced to amine (IX) corresponding with hydrogen in the presence of different catalysts (eg example, palladium on activated charcoal) or by treatment with triphenylphosphine followed by hydrolysis imidophosphorane intermediates (Golo lobov, YG (1981), "Sixty years of staudinger reaction ", Tetrahedron 37 (3), 437).
Alternatively, the primary amines R'3-NH2 of formula (IX) can be prepared according to scheme 3 from commercial acids (X) [in which X and R have the even meaning that X and R5 respectively above for the compounds of general formula (I)], converting them into amides of Weinreb (XI) (Nahm, S. Weinreb, SM
(1981), "N
methoxy-n-methylamides as effective acylating agents ", Tetrahedron Letters 22, 3815), which after reaction with Grignard aryl or heteroaryl reagents or with lithiated derivatives aryl or heteroaryl give the ketones (XII) which can be reduced to secondary alcohols (VI).
Following the steps described in Figure 2, alcohol (VI) is eventually transformed into R'3-NH2 amine of formula (IX).
The chiral primary amine R'3-NH2 of structure (XV) can also be prepared according to scheme 4 by condensation of enantiomerically 2-methyl-2-propanesulfinamide pure (tert-butanesulfinamide, Elman sulfinamide: Liu, G. et al. J. Am. Soc. Chem. 1997, 119, 9913) with aldehyde (IV) under mild conditions. This reaction provides the tert-butanesulfinyl imines (XIII). The tert-butanesulfinyl group activates imines for addition of reagents Grignard and serves as an important chiral steering group to products (XIV) with high diastereoselectivity. Deprotection of the grouping butanesulfinyl in mild acidic conditions gives the chiral amine (XV).
The amide derivatives of 3-aminosalicylic acid of formula (XVIII) are prepared according to scheme 5a / from 3-nitrosalicylic acid (XVI) using conditions of standard peptide coupling (Recent development of peptide coupling reagents in organic Tetrahedron synthesis, Volume 60 (11), 2447-2467, Han, S.-Y., Kim, Y.-A. ) followed by reduction of the nitro group to an amino group by hydrogen in presence of a suitable catalyst (eg palladium on activated carbon). The derivative (XVIII) reacts then with dimethoxysquarate or commercial diethoxysquarate to give intermediate (XIX), which is converted into compound (XX) after reaction with amine primary R '3 -NH 2.

WO 2013/061004

23 Alternatively, the coupling of 3-aminosalicylic acid (XXI) with diméthoxysquarate or diethoxysquarate commercial gives, according to scheme 51) 1, the acid derivative intermediate (XXII) which, after reaction with the primary amine R'3-NH2, can give the compound (XXIII).
The latter can finally be engaged in a peptide coupling reaction with an amine RaRbNH formula to yield the compound of formula (XX).
By way of illustration, the following compounds corresponding to the general formula (I) of this invention were prepared by following one of the schemes presented above.

Preparation of 2-hydroxy-N, N-dimethyl-3- (2-1 [(5-methyl-furan-2-yl) -(2-methyl-tetrahydrofuran-2-yl) -methyl-amino] -3,4-dioxo-cyclobut-1-enylamino) benzamide [tape 1 [tape 2, .., [tape 3 [tape 4 Ns Step 5 ______________________________________________________. HsN

[tape 1 [tape 9 HO NO NO NH el [step 6 g I [step 7 0 [step 8 i ',,,, N Niliir0 ¨ 0 s 0 OH 0 OH 0 OH 0 OH H --- \
Step 1:
(2-Methyl-tetrahydrofuran-2-y1) -methanol 19.94 g (0.145 mol, 1 eq) of 2-methyltetrahydrofuran-2-carboxylic acid (commercial) to 95% in solution in 100 mL of diethyl ether were added dropwise to drop on a suspension cooled to 10 C of 16.6 g (0.438 mol, 3 eq) of lithium hydride and aluminum in 100 mL of diethyl ether. The reaction medium was stirred at ambient temperature for 24 hours. The reaction medium was cooled and water was added drop by drop followed by a saturated solution of ammonium chloride. The medium was extracted at ether diethyl. The organic phases were combined, washed with water, dried on sulphate magnesium, filtered and evaporated. 14.45 g of (2-methyl-tetrahydrofuran-2-yl) methanol have been obtained. Yield = 86%. TLC / SiO2: CH2Cl2 / MeOH (95/5), revelation KMn04.
2nd step:

WO 2013/061004

24 2-Methyl-tetrahydrofuran-2-carbaldehyde A solution of 14.44 g (0.124 mol, 1 eq) of (2-methyl-tetrahydrofuran-2-yl) methanol in 140 mL of dichloromethane was added dropwise over a mixture of 43.0 g (0.20 mol, 1.6 eq) of pyridinium chlorochromate in 400 mL of dichloromethane. 15 g of celite have were added and the reaction medium was stirred at room temperature for 7 hours. The reaction medium was filtered through 280 g of silica and eluted with dichloromethane (4.5 L). 6.0 g of 2-methyl-tetrahydrofuran-2-carbaldehyde were obtained in the form of a yellow liquid (1 ' 77% fraction). 8.4 g of 2-methyl-tetrahydrofuran-2-carbaldehyde were obtained under form of an orange liquid (2 'fraction at 54%). Yield = 65%. TLC / SiO2:
Heptane / AcOEt (40/60), revelation at KMn04 Step 3:
(5-Methyl-furan-2-y1) - (2-methyl-tetrahydrofuran-2-y1) -methanol 24 mL (60 mmol, 1.5 eq) of a solution of 2.5 M n-butyllithium in hexane have been added dropwise on a solution of 5.0 g (60 mmol, 1.5 eq) of 2-methylfuran in 100 mL
of tetrahydrofuran cooled to -70 C. The reaction medium was stirred and let go back to room temperature for 2 hours. The reaction medium was cooled to -70 C then 6.0 g (40 mmol, 1 eq) of 77% 2-methyl-tetrahydrofuran-2-carbaldehyde were added. The environment The reaction mixture was stirred at room temperature for 3 hours. The environment reaction was treated with a saturated solution of ammonium chloride and extracted with acetate ethyl. The organic phases were collected, washed with a saturated solution of chloride of sodium, filtered over magnesium sulphate and evaporated. 5.21 g of (5-methyl) furan-2-y1) - (2 methyl tetrahydrofuran-2-yl) methanol were obtained. Yield = 66%.
TLC / SiO2:
Heptane / AcOEt (60/40), revelation at KMn04 Step 4:
2- [azido (2-methyl-tetrahydrofuran-2-y1) -méthy1J-5-methyl-furan 8.77 g (31.8 mmol, 1.2 eq) of diphenylphosphoryl azide was added dropwise.
drop on a solution of 5.21 g (26.5 mmol, 1 eq) of (5-methyl-furan-2-yl) - (2-methyl) tetrahydrofuran-2-yl) -methanol in 90 mL of toluene. The reaction medium been cooled to 0 C then 4.75 mL (31.8 mmol, 1.2 eq) of 1,8-diazabicyclo [5.4.0] undec-7-ene have been added drip. The reaction medium was stirred at room temperature for 41 hours.
The reaction medium (heterogeneous) was treated with water and acetate of ethyl and then decanted. The The organic phase was washed with 1N hydrochloric acid, dried over sodium sulfate magnesium, WO 2013/061004

25 filtered and evaporated. The residue was chromatographed on HP silica gel (puriFlash column IR5OSI-200G, spot II) eluted with heptane / ethyl acetate (95/5). 2.15 g of 2-[Azido (2-methyl-tetrahydrofuran-2-yl) methyl] -5-methyl furan were obtained. Yield = 37%.

TLC / SiO2: Heptane / AcOEt (80/20), revelation with KMnO4.
Step 5:
C- (5-Methyl-furan-2-y 1) -C (2-methyl-tetrahydrofuran-2-y1) methylamine A solution of 2.51 g (9.7 mmol, 1 eq) of 2- [azido- (2-methyl-tetrahydrofuran) 2-y1) -methyl] -5-methyl-furan in 45 mL of ethanol was stirred under atmospheric pressure hydrogen in the presence of 323 mg (15% by weight) of 10% palladium on carbon (Pd / C) during 16 hours. The reaction medium was filtered and the filtrate was evaporated. 1.82 g of C- (5-methyl) furan-2-yl) -C- (2-methyl-tetrahydrofuran-2-yl) methylamine were obtained.
Yield =
96%. TLC / SiO2: Heptane / AcOEt (60/40), revelation with KMnO4.
Step 6:
2-Hydroxy-N, N-diméthy1-3-nitro-benzamide 42.9 mL (0.50 mol, 3 eq) of oxalyl chloride was added dropwise on a suspension of 30 g (0.16 mol, 1 eq) of 3-nitrosalicylic acid in 1200 mL of dichloromethane. 30 drops of N, N-dimethylformamide were added (strong clearance from gas, adaptation of a carbon monoxide vapor trapping system toxic). The The reaction medium was stirred at room temperature for 24 hours. The reaction medium was cooled to 0-5 C then 246 mL (0.49 mol, 3 eq) of a solution of dimethylamine in the 2N tetrahydrofuran were added. The reaction medium was stirred at ambient temperature for 2 days. The reaction medium was concentrated to dryness and the residue was been put in solution in 300 mL of 1N sodium hydroxide. The aqueous solution (red) was extracted 3 times with 300 mL of dichloromethane. The aqueous phase was cooled in an ice-water bath, and the pH has been adjusted to 2 with about 50 mL of 6N hydrochloric acid. The mixture (become yellow) has been extracted 3 times with 300 mL of dichloromethane. The organic phases have been gathered, washed twice with 250 mL of water and once with 250 mL of a solution saturated with chloride of sodium, dried over anhydrous magnesium sulphate and evaporated. 33.5 g of 2-hydroxy N, N-dimethyl-3-nitro-benzamide was obtained as a cottony solid yellow.
Yield = 97%.
Step 7:

WO 2013/061004

26 3-A mino-2-hydroxy-N, N-dimethylbenzamide A solution of 33.5 g of 2-hydroxy-N, N-dimethyl-3-nitro-benzamide in 600 mL

of ethanol was added to a suspension of 3.35 g of 10% Pd / C in 70 ml ethanol. The The reaction medium was stirred under 2 bar of hydrogen overnight.
CCM control and HPLC (t = 0.66 M + 181). The reaction medium was filtered on celite and the filtrate was evaporated.
29 g of 3-amino-2-hydroxy-N, N-dimethylbenzamide were obtained in the form of a solid oily brown. Yield = 100%.
Step 8:
3- (2-Ethoxy-3,4-dioxo-1-enylamino-eyelobut) -2-hydroxy-N, N-dimethyl-benzamide Under nitrogen and at room temperature, 39.7 g of diethoxysquarate were added (in 15 minutes) on a solution of 28 g of 3-amino-2-hydroxy-N, N-dimethyl-benzamide in 840 mL of ethanol cooled to 0 ° C. The reaction medium was stirred for 2 minutes.
hours at 0 C and 48 hours at room temperature. 700 mL of ethanol was added (which increases the precipitation of the expected product). The solid was filtered, washed with ethanol ambient and dried. 36.9 3- (2-Ethoxy-3,4-dioxo-cyclobut-1-enylamino) -2-hydroxy-N, N-dimethyl-benzamide have were obtained in the form of a light khaki green solid. Yield = 78%.
Step 9:
2-Hydroxy-N, N-dimethyl-3 - (2 - {[(5-methyl-furan-2-yl) - (2-methylethyl) -tetraary drofuran-2-y1) -methyl-aminol-3,4-dioxo-eyelobut-1-enylamino) -benzamide (diastereoisomers 1 and 2) 1.82 g (9.3 mmol, 1.5 eq) of C- (5-methyl-furan-2-yl) -C- (2-methyl);
tetrahydrofuran-2-y1) -methylamine was added over 1.89 g (6.2 mmol, 1 eq) of 3- (2-ethoxy-3,4 dioxo-cyclobut-l-enylamino) -2-hydroxy-N, N-dimethylbenzamide heat-solubilized in 100 mL of methanol. The reaction medium was heated at 60 ° C. for 3 hours and half. Methanol was evaporated and the residue was chromatographed on silica gel (column puriFlash IR505I-200G, spot II) eluted with dichloromethane / methanol (gradient).
Diastereoisomer 1, 1.00 g of 2-hydroxy-N, N-dimethyl-3- (2 - {[(5-methyl-furan-2-y1) - (2 methyl-tetrahydrofuran-2-yl) -methyl-amino-3,4-dioxo-cyclohebutyl enylamino) -b enzamide a was obtained as a beige solid (mp = 127-129 ° C). LC / MS: 98.41%
[453].
1H NMR (DMSO, 400MHz): 1.22 (s, 3H); 1.57-1.62 (m, 1H); 1.67-1.74 (m, 1H) ; 1.82-1.89 (m, 1H); 1.95-1.99 (m, 1H); 2.28 (s, 3H); 2.94 (s, 6H); 3.6 (q, J =
6.7 Hz, 1H); 3.8 (q, J = 7.5 Hz, 1H); 5.3 (d, J = 10 Hz, 1H); 6.06 (d, J = 3.0 Hz, 1H), 6.25 (dd, J = 3.0 Hz, 1H);

WO 2013/061004

27 6.87 (m, 2H); 7.76 (dd, J = 6.7 Hz, 1H); 8.93 (d, J = 10.0 Hz, 1H); 9.56 (s, 1H); 9.92 (s, 1H).
Diastereoisomer 2, 1.03 g of 2-hydroxy-N, N-dimethyl-3- (2 - {[(5-methyl-furan-2-y1) - (2 methyl-tetrahydrofuran-2-yl) -methyl-amino-3,4-dioxo-cyclohebutyl enylamino) -b enzamide have been obtained. (Mp = 127-129 ° C), LC / MS: 97.76% [453].
1 H NMR (DMSO-d 6, 400 MHz): 1.16 (s, 3H); 1.65-1.70 (m, 1H); 1.84-1.98 (m, 3H); 2.28 (s, 3H); 2.94 (s, 6H); 3.76-3.80 (m, 2H); 5.3 (d, J = 9.9 Hz, 1H); 6.06 (dd, J = 2.9 Hz, 1H), 6.28 (d, J = 3.0 Hz, 1H); 6.85-6.91 (m, 2H); 7.75 (dd, J = 6.9 Hz, 1H);
8.85 (d, J = 10.0 Hz, 1H); 9.54 (s, 1H); 9.95 (s, 1H).
2-Hydroxy-N, N-diméthy1-3- (2 - {[(5-methyl-furan-2-y1) - (2-methyl-tetrahydrofuran-2-y1) -methyl-aminol-3,4-dioxo-cyclobut-1-enylamino) -benzamide (enantiomers 1 and 2 of diastereoisomer 2) The separation of diastereoisomer 2 into enantiomers 1 and 2 was carried out on the column chiral CHELALCELR OD-H 5 ium ¨ 250 x 4.6 mm, the mobile phase:
carbon / methanol (80/20), flow rate of 120 mL / min.
Enantiomer 1 of diastereoisomer 2: retention time at 3.91 min Enantiomer 2 of diastereoisomer 2: retention time at 5.08 min Preparation of 2-hydroxy-N, N-dimethyl-3- (2 - {[(5-methyl-furan-2-yl) -(tetrahydro-thiophen-2-yl) -methyl-amino] -3,4-dioxo-cyclobut-1-enylarnino) -benzamide `n Step 1 Step 2 S Step 3 Step 4 S Step ss _____ 0 ______ OH __ - Na __ NH2 HO N HO me \ \

Step 1 Step 9 HO 11111 Step 6 Step 7 Step 8 ¨

0 OH 'NH2 Step 1:
Methoxy-methyl-tetrahydro-thiophene-2-carboxamide WO 2013/061004

28 To a solution of 46.0 g (0.35 mol; 1.0 eq) of tetrahydro-thiophene-2-carboxylic (commercial) in 200 mL of dichloromethane were added dropwise 32.0 mL (0.44 mol; 1.27 eq) of thionyl chloride at room temperature in 15 minutes. The middle The reaction mixture was stirred at room temperature for 3 hours until that there is no longer gaseous release. Dichloromethane and excess thionyl chloride have been evaporated under vacuum and the residue was coevaporated three times with 100 mL of toluene. Chloride of acid obtained was solubilized in 200 mL of dichloromethane and 37.34 g (0.38 mol, 1.1 eq) N, O-dimethylhydroxylamine hydrochloride was added. The environment reaction was cooled to -10 C and a mixture of 116 mL (0.84 mol, 2.4 eq) of triethylamine in 100 mL of dichloromethane was added dropwise in one hour (now temperature below 5 C). After the addition, the reaction medium was stirred at ambient temperature for one hour and then washed with 250 mL of an aqueous solution of hydrochloric at 1M. The aqueous phase was extracted with dichloromethane. The phases organic have been pooled, washed with 200 mL of an aqueous solution of hydrogen phosphate sodium 1M, dried over anhydrous magnesium sulfate, filtered and evaporated. 51.0 g of methoxy methyl tetrahydro-thiophene-2-carboxylamide were obtained in the form of a orange oil.
Yield = 84%.
2nd step:
(5-Methyl-furan-2-y1) - (tetrahydro-thiophen-2-y1) -methanone 176 mL (440.8 mmol, 1.50 eq) of 2.5 M n-butyllithium in hexane were added drop dropwise on a solution of 39.8 mL (440.8 mmol, 1.50 eq) of 2-methyl furan in 1 L of tetrahydrofuran cooled to -78 C. The mixture was allowed to rise to ambient temperature for 2 hours then was cooled to -78 C. A solution of 51.00 g (291 g) mmol; 1.00 eq) of methoxy-methyl-tetrahydro-thiophene-2-carboxylamide in 400 mL of tetrahydrofuran was added and the reaction mixture was left at 0 C for 2 hours.
The environment The reaction mixture was diluted with 500 mL of ethyl acetate and then washed with 1 L
a solution aqueous hydrochloric acid 1N. The aqueous phase was separated and extracted with 500 mL
of ethyl acetate. The organic phases were collected, washed with saturated solution of sodium chloride, dried over anhydrous magnesium sulphate, filtered and evaporated.
The brown oil obtained was filtered on silica (eluent: Heptane / AcOEt 90/10).
49.67 g of (5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methanone were obtained.
Yield = 87%.
Step 3:

WO 2013/061004

29 (5-Methyl-furan-2-y1) - (tetrahydro-thiophen-2-y1) -methanol 6.69 g (0.18 mol, 1.20 eq) of sodium borohydride were added by small portions on a solution of 30.24 g (0.15 mol; 1.0 eq) of (5-methyl-furan-2-yl) -(Tetrahydro-thiophen-2-y1) -methanone in 300 mL of tetrahydrofuran and 50 mL of methanol cooled to 0 C. The The reaction medium was stirred at room temperature for 3 hours. The reaction medium was poured into 400 mL of ethyl acetate and 200 mL of water were added.
The sentence The aqueous solution was extracted with ethyl acetate and the organic phases were gathered, washed with saturated sodium chloride solution, dried over sodium sulphate magnesium anhydrous, filtered and evaporated. 30.22 g of (5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-y1) -methanol were obtained. Quantitative yield Step 4:
2- [azido (tetrahydro-thiophen-2-y1) -méthy1J-5-methyl-furan To a solution of 30.21 g (0.15 mol; 1.0 eq) of (5-methyl-furan-2-yl) (Tetrahydro-thiophen-2-y1) -methanol in 350 mL of toluene cooled to 0 C was added 39.3 mL
(0.18 mol; 1.2 eq) diphenylphosphoryl azide then 27.3 mL (0.18 mol; 1.2 eq) of 1.8-diazabicyclo [5.4.0] undec-7-ene dropwise. The mixture was left return to temperature gently and then stirred for 2 days. The reaction medium been treated with water and extracted with ethyl acetate. The organic phases have been collected, washed with a 1M sodium hydrogenphosphate solution, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI / 800G, puriFlash) eluted with heptane / ethyl acetate (95/5). 26.95 g of 2- [azido (Tetrahydro-thiophen-2-yl) -methyl] -5-methyl-furan were obtained (mixture of the two diastereoisomers).
Yield =
79%
Step 5:
C- (5-Methyl-furan-2-y1) C- (tetrahydro-thiophene-2-y1) methylamine A solution of 26.95 g (0.12 mol; 1.0 eq) of 2- [azido- (tetrahydro-thiophene) -2-y1) methyl] -5-methyl furan in 540 ml of ethanol and in the presence of 6.74 g (25% by weight) of Pd / C 10%
was stirred at room temperature under atmospheric pressure of hydrogen for 2 days.
The reaction medium was filtered and the filtrate was evaporated. The residue been chromatographed on silica gel (puriFlash IR-50S1-STD / 800G column, puriFlash) eluted at dichloromethane / ethyl acetate (gradient).

WO 2013/061004

30 Diastereoisomer 1: 5.52 g of C - [(R) -C- (5-methyl-furan-2-yl) -C-tetrahydro-thiophen-2-y1] -methylamine were obtained. Yield = 22%.
Diastereoisomer 2: 13.30 g of C - [(R) -C- (5-methyl-furan-2-yl) -C-tetrahydro-thiophen-2-y1] -methylamine were obtained. Yield = 54%.
.
Steps 6 to 8:
In a similar manner to EXAMPLE 1 (Steps 6 to 8), 3- (2-ethoxy-3,4-dioxo) cyclobut-l-enylamino) -2-hydroxy-N, N-dimethylbenzamide was prepared.
Step 9:
2-Hydroxy-N, N-dimethyl-3- (2- (5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-y1) -méthylf-aminol-3,4-dioxo-eyelobut-1-enylamino) -benzamide (diastereoisomer 1) A mixture of 694 mg (2.28 mmol, 1.0 eq) of 3- (2-ethoxy-3,4-dioxo-cyclobut-1) enylamino) -2-hydroxy-N, N-dimethylbenzamide and 540 mg (2.74 mmol, 1.2 eq) of C- (5-methyl-furan 2-yl) -C- (tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 1) in solution in 20 mL
of methanol was stirred at room temperature for 4 days. The insoluble been filtered and dried under vacuum at 50 ° C. 560 mg of 2-hydroxy-N, N-dimethyl-3 - (2 - {[(5-methyl) furan-2-y1) -(Tetrahydro-thiophen-2-yl) -methyl-amino-3,4-dioxo-cyclobut-1-enylamino) enzamide (diastereoisomer 1) were obtained. Yield = 54%.
1 H NMR (DMSO-d 6, 400 MHz): 1.63-1.68 (m, 1H), 1.88-1.92 (m, 1H), 1.98-2.04 (m, 2H), 2.26 (s, 3H), 2.81 (t, J = 5.9 Hz, 2H), 2.94 (s, 6H), 3.97 (q, J = 6.6 Hz, 1H), 5.41 (q, J = 6.8-2.7 Hz, 1H), 6.06 (dd, J = 0.9-3.0 Hz, 1H), 6.26 (d, J = 3.1 Hz, 1H), 6.86-6.91 (m, 2H), 7.75 (dd, J = 2.6-7.0 Hz, 1H), 8.82 (d, J = 9.6 Hz, 1H), 9.51 (s, 1H), 9.94 (s, 1H).
2-Hydroxy-N, N-dimethyl-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2 y1) -méthylf-aminol-3,4-dioxo-eyelobut-1-enylamino) -benzamide (diastereoisomer 2) A mixture of 1.29 g (4.22 mmol, 1.0 eq) of 3- (2-ethoxy-3,4-dioxo-cyclobut-1) enylamino) -2-hydroxy-N, N-dimethylbenzamide and 1.0 g (5.07 mmol, 1.2 eq) of C- (5-methyl-furan-2-y1) -C- (tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) in solution in 40 mL
of methanol was stirred at room temperature for 2.5 days.
The insoluble has been filtered and dried under vacuum at 45 ° C. 1.48 g of 2-hydroxy-N, N-dimethyl-3 - (2 - {[(5-methyl) furan-2-y1) -(Tetrahydro-thiophen-2-yl) -methyl-amino-3,4-dioxo-cyclobut-1-enylamino) enzamide (diastereoisomer 2) were obtained. Yield = 77%.

WO 2013/061004

31 1 H NMR (DMSO-d 6, 400 MHz): 1.82-1.86 (m, 2H), 1.90-1.93 (m, 2H), 2.26 (s, 3H), 2.75-2.84 (m, 2H), 2.93 (s, 6H), 3.86 (m, 1H), 5.2 (t, J = 9.7 Hz, 1H), 6.06 (dd, J);
= 1.0-3.0 Hz, 1H), 6.30 (d, J = 3.1 Hz, 1H), 6.84-6.90 (m, 2H), 7.79 (dd, J = 2.3-7.2 Hz, 1H), 8.77 (d, J = 9.6 Hz, 1H), 9.34 (s, 1H), 9.94 (s, 1H).
2-Hydroxy-N, N-diméthy1-3- (2 - {[(5-methyl-furan-2-y1) - (tetrahydro-thiophen-2-y1) -méthylf-aminol-3,4-dioxo-eyelobut-1-enylamino) -benzamide (enantiomers 1 and 2) The separation of diastereoisomer 1 into enantiomers was carried out on the chiral column CHIRALPACKR ICium, mobile phase: carbon dioxide / ethanol (100 / 0.5), flow rate mL / min.
Enantiomer 1 of diastereoisomer 1: retention time 6.1 min Enantiomer 2 of diastereoisomer 1: retention time at 8.0 min 2-Hydroxy-N, N-dimethyl-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophene) 2-yl) -methyli -amino1-3,4-dioxo-eyelobut-1-enylamino) benzamide (enantiomers 1 and 2) The separation of diastereoisomer 2 into enantiomers was carried out on the chiral column CHIRALPACKR ADH 5 ium, mobile phase: heptane / ethanol (60/40), flow rate 42.5 mL / min.
Enantiomer 1 of diastereoisomer 2: retention time at 3.6 min Enantiomer 2 of diastereoisomer 2: retention time at 4.7 min Preparation of (S) -1-11-fluoro-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-y1) -Methyl-amino] -3,4-dioxo-cyclobut-1-enylamino) -benzoyll-pyrrolidine-2-carboxylate methyl WO 2013/061004

32 S
Step 1 Step 2 S Step 3 OH Step 4 S
Step 5 S
HO '' N ON \ ON \ ON \ ON \ ON \
0 __0) 0 Step 9 Step 1 diastereoisomer 2 Step 8 NH, 0 0 HO NO

1 Step 6 UN 110 Step 7 O1-; '''NO2 NO, --- IN N) ("
M
Me00C 0 F e00C 0 F
H 0¨

Me00C 0 F

Iit S 0 0 Step 10 to the S 11 S

CN. NN
HH. NOT

0 ..-H CN H
i 0 F \\ FH 1 /
= 0 F
Me00C = 0 Me00C
2 Me00C diastereoisomer enantiomer 1 enantiomer 2 Steps 1 to 5:
In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) was prepared.
Step 6:
(S) -1- (2-Fluoro-3-nitro-benzoyl) -pyrrolidine-2-methyl-carboxylate A mixture of 18.51 g (0.10 mol; 1.0 eq) of 2-fluoro-3-nitro-benzoic acid and 100 mL of Thionyl chloride was refluxed for 3 hours. The excess of thionyl chloride It was then concentrated and the residue was coevaporated twice with toluene.
Chloride of acid thus obtained was taken up in 250 ml of dichloromethane. To this mixture cooled to 0 C were added 16.56 g (0.10 mol; 1.0 eq) of ester hydrochloride methyl from L-then proline 30.50 mL (0.22 mol; 2.2 eq) of triethylamine. After 30 minutes to 0 C and one hour at room temperature, the reaction medium was diluted and washed with 250 mL of a 1M aqueous solution of hydrochloric acid and then with 250 mL of a solution saturated aqueous of sodium hydrogencarbonate. The organic phase was dried over sodium sulfate magnesium anhydrous, filtered and evaporated. 25.64 g of (S) -1- (2-fluoro-3-nitro-benzoyl) -pyrrolidine-2-methyl carboxylate were obtained. Yield = 87%.
Step 7:
Methyl (S) -1- (3-Amino-2-fluoro-benzoyl) -pyrrolidine-2-carboxylate A solution of 25.0 g (0.08 mol; 1.0 eq) of (S) -1- (2-fluoro-3-nitro-benzoyl) -pyrrolidine-2-methyl carboxylate in 250 mL of methanol in the presence of 7.0 g (28%
mass) 10% palladium on charcoal was stirred under a hydrogen atmosphere at temperature ambient for 4 days. The reaction medium was filtered on celite and washed with 100 mL of WO 2013/061004

33 methanol. The filtrate was evaporated. 22.80 g of (S) -1- (3-amino-2-fluoro) benzoy1) -pyrrolidine-2-Methyl carboxylate was obtained as a clear oil.
Quantitative yield Step 8:
(S) -1-P-Fluoro-3- (2-methoxy-3,4-dioxo-eyelobut-l-enylamino) -benzoyll-pyrrolidine-2-methyl carboxylate To a solution of 20.0 g (0.08 mol; 1.0 eq) of (S) -1- (3-amino-2-fluoro) benzoy1) -pyrrolidine 2-methyl carboxylate in 150 ml of methanol were added 21.35 g (0.15 mol; 2.0 eq) 3,4-dimethoxy-3-cyclobutene-1,2-dione. The reaction medium was heated to 50 C
for 3 hours and concentrated. The residue was eluted on a silica cake (15 cm diameter and 10 cm high) with 2 L of heptane / ethyl acetate (2/1), 2 L
heptane / ethyl acetate of ethyl (1/2) and 2 L of ethyl acetate / methanol (95/5). 19 g of a product have been obtained. This The product was purified by chromatography on silica gel eluted with ethyl acetate. 15 g (S) -1- [2-fluoro-3 - (2-methoxy-3,4-dioxo-cyclo-but-1-enylamino) -b enzo yl] -pyrro lidine-2-methyl carboxylate were obtained. Yield = 53%.
Step 9:
(S) -1- [2-Fluoro-3- (2- (5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -m ethyl-amino Methyl 3,4-dioxo-eyelobut-1-enylamino) benzoyll-pyrrolidine-2-carboxylate A mixture of 1.02 g (2.70 mmol, 1.0 eq) of (S) -142-fluoro-3- (2-methoxy-3,4-dioxo methyl cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate and 640 mg (3.24 mmol; 1.2 eq) C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) in solution in 25 mL of methanol was stirred at ambient temperature for 3 days and a half. The reaction medium was evaporated and the residue been chromatographed on silica gel (puriFlash IR-5051 / 120G column, spot II) eluted at dichloromethane / ethyl acetate of ethyl (gradient). 1.01 g of (S) -1- [2-fluoro-3- (2 - {[(5-methyl-furan-2-yl) -(tetrahydro-thiophen-2-yl) -methyl-amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -Pyrro lidine-2-Methyl carboxylate (couple of enantiomers 1 and 2) were obtained.
Yield = 69%.
1 H NMR (DMSO-d 6, 400 MHz): 1.81-2.07 (m, 7H), 2.26 (s, 3H), 2.29 (m, 1H), 2.75-2.84 (m, 2H), 3.35-3.38 (m, 2H), 3.68 (s, 3H), 3.86-3.90 (m, 1H), 4.49-4.53 (m, 1H), 5.17 (t, J = 9.5 Hz, 1H), 6.07 (d, J = 2.9 Hz, 1H), 6.33 (d, J = 3.1 Hz, 1H), 7.02 (t, J = 6.6 Hz, 1H), 7.26 (t, J
= 7.9 Hz, 1H), 8.05 (t, J = 7.9 Hz, 1H), 7.56 (d, J = 9.6 Hz, 1H), 9.64 (s, 1H).
Step 10:

WO 2013/061004

34 (S) -1- [2-Fluoro-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl-amino 3,4-dioxo-eyelobut-1-enylamino) -benzoyll-pyrrolidine-2-carboxylate methyl (enantiomer 1 and enantiomer 2) The enantiomers were separated on the column CHIRALPACK ADH 5 ium with eluent carbon dioxide / (ethanol + 1% diethylamine) 85/15, flow rate of 120 mL / min.
Enantiomer 1: retention time at 20.9 min Enantio mother 2: retention time at 33.7 min Preparation of (S) -1-11-fluoro-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-y1) -Methyl-amino] -3,4-dioxo-cyclobut-1-enylamino) -benzoyll-pyrrolidine-2-carboxylate isopropyl s Step 1 Step 2 Step 3 Step 4 S Eta e 5 S
HO
ON \ oN
F
0 Step 9 Step 1 diasterSoisomere 2 HN
Step 8 0 Step 6 0 Ir) HO NH2 G the H 1 -f HN
0 F NC) 2 0 F CN number , 0 0 F
NS

Steps 1 to 5:
In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) was prepared.
Step 6:
(S) -1- (2-Fluoro-3-nitro-benzoyl) -pyrrolidine-2-isopropyl carboxylate A mixture of 1.50 g (8.10 mmol, 1.0 eq) of 2-fluoro-3-nitro-benzoic acid and 16 mL of Thionyl chloride was refluxed for 3 hours. The excess of thionyl chloride It was then concentrated and the residue was coevaporated twice with toluene.
Chloride of acid thus obtained was taken up in 25 ml of dichloromethane. To this mixture cooled to 0 C
1.27 g (8.10 mmol, 1.0 eq) of (S) -pyrrolidine-2-carboxylate were added isopropyl. The reaction medium was stirred at 0 ° C. for 30 minutes and then at room temperature ambient during WO 2013/061004

35 2 hours. The reaction medium was diluted and washed with an acid solution hydrochloric acid 1M
(100 mL) and then with saturated sodium hydrogencarbonate solution (100 mL). The The organic phase was dried over MgSO 4, filtered and evaporated. 2.12 g of (S) -1-(2-fluoro-3-nitro-benzoyl) -pyrrolidine-2-carboxylic acid isopropyl ester. Yield = 81%.
Step 7:
(S) -1- (3-Amino-2-fluoro-benzoyl) -pyrrolidine-2-isopropyl carboxylate A solution of 2.12 g (6.55 mmol, 1.0 eq) of (S) -1- (2-fluoro-3-nitro-benzoyl) -pyrrolidine-2-isopropyl carboxylate in 40 mL of methanol in the presence of 0.32 g (15%
mass) 10% palladium on charcoal was stirred under a hydrogen atmosphere at temperature ambient for 16 hours. The reaction medium was filtered on celite and concentrated to dry.
1.87 g of (S) -1- (3-amino-2-fluoro-benzoyl) -pyrrolidine-2-carboxylate of isopropyl obtained in the form of a colorless oil. Yield = 97%.
Step 8:
(S) -1-P-Fluoro-3- (2-methoxy-3,4-dioxo-eyelobut-l-enylamino) -benzoy1J-pyrrolidine-2-isopropyl carboxylate To a solution of 1.87 g (0.08 mol; 1.0 eq) of (S) -1- (3-amino-2-fluoro) benzoy1) -pyrrolidine Isopropyl 2-carboxylate in 45 ml of methanol was added 1.80 g (0.01 mol, 2.0 eq) 3,4-dimethoxy-3-cyclobutene-1,2-dione. The reaction medium was stirred at temperature ambient for 24 hours. The solvent was evaporated and the residue was chromatographed on gel silica (prepacked column of 200 g, heptane / ethyl acetate eluent20 / 80 then 0/100). 1.32 g (S) -1- [2-fluoro-3- (2-methoxy-3,4-dioxo-cyclobut-1-enylamino) benzoyl]
-pyrrolidine-2-isopropyl carboxylate was obtained as a yellow amorphous solid clear.
Yield = 51%.
Step 9:
(S) -1-P-Fluoro-3- (2 - {[(5-methyl-furan-2-y1) - (tetrahydro-thiophen-2-y1) -méthylf-aminol-3,4-dioxo-1-enylamino-eyelobut) -benzoy1J-pyrrolidine-2-earboxylate isopropyl A mixture of 600 mg (1.48 mmol, 1.0 eq) of (S) -1- [2-fluoro-3- (2-methoxy) -3-dioxo cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate isopropyl and 350 mg (1.78 mmol; 1.2 eq) C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) dissolved in 25 ml of methanol was heated to 60 ° C.
during 18 hours. The reaction medium was evaporated and the residue was chromatographed on silica gel WO 2013/061004

36 eluted with dichloromethane / ethyl acetate (75/25). The paste obtained was crystallized in ethyl ether, filtered and dried under vacuum at 40 ° C. 575 mg of (S) -1- [2-fluoro-3- (2- {[5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -3,4-dioxo -cyc lo but-1-isopropyl enylamino) -benzoyl] -pyrrolidine-2-carboxylate were obtained in the form of a white solid. Yield = 67%.
1 H NMR (DMSO-d 6, 400 MHz): 0.89 (m, 1H), 1.06 (m, 1H), 1.19-1.23 (m, 4H), 1.81-2.07 (m, 7H), 2.26 (s, 3H), 2.29 (m, 1H), 2.75-2.83 (m, 2H), 3.35 (m, 2H), 3.88-3.90.
(m, 1H), 4.42-4.45 (m, 1H), 4.92-4.95 (m, 1H), 5.17 (t, 1H), 6.07 (d, J = 2.9 Hz, 1H), 6.33.
(d, J = 4 Hz, 1H), 7.01 (t, 1H), 7.26 (t, J = 8Hz, 1H), 8.04 (t, 1H), 8.55 (d, J = 8Hz, 1H), 9.63 (s, 1H).

Preparation of (S) -1-11-fluoro-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-y1) -Methyl-amino] -3,4-dioxo-cyclobut-1-enylamino) -benzoyll-pyrrolidine-2-carboxylate ethyl 0 n HO
Step 1 Step 2 S 0 Step 3 S OH EtaPe 4 S ..a Step 5 S
SS _________________________. ____ NH2 0 \ Step 9 F
Step 1 d lastereolsomer 2 /
H
O
NST. he (yNH2 _._ Step 8 0 Step 6 C Step 7 NOT
O
HO NO, F NO, FOo FH 0¨

Steps 1 to 5:
In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) was prepared.
Steps 6 to 9:
In a manner analogous to EXAMPLE 2 (Steps 6 to 9), and from the hydrochloride of the ester L-proline ethyl, (S) -1- [2-fluoro-3- (2 - {[(5-methyl-furan-2-yl) -(Tetrahydro-thiophen 2-yl) -methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrro lidine-2-carboxylate of ethyl was prepared. Yield = 30%.

WO 2013/061004

37 Preparation of (R) -1-11-hydroxy-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-y1) -methyl-amino-3,4-dioxo-cyclobut-l-enylamino) -benzoyll-pyrrolidine-2-carboxylate methyl s Step 1 s Step 2 S 0 Step 3 S Step 4 S Step 5 S
OH Me00C
HO
WE \ \ \ \
Step 1 diastereoisomere 2 Step 9 Ho 'bind HN
HO
Step 6 NO
Me0 011 Step 7 NH,? I
Step 8 HTL ... ni , IN I OH N) 2 ( NO, Me00C 0 OH

Me00C 0 Steps 1 to 5:
In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) was prepared.
Step 6:
Methyl 1- (2-Hydroxy-3-nitro-benzoyl) -pyrrolidine-2-carboxylate A mixture of 3.74 g (20.4 mmol, 1 eq) of 3-nitrosalicylic acid and 14.27 g (30.6 mmol, 1.5 eq) of bromotripyrrolidinophosphonium hexafluorophosphate in 56 mL of dichloromethane and in the presence of 12.3 ml (71.5 mmol, 3.5 eq) of N, N-Diisopropylethylamine was stirred at room temperature for 5 minutes.
5.07 g (30.6 mmol, 1.5 eq) of methyl (R) -pyrrolidine-2-carboxylate hydrochloride in solution in 10 ml of dichloromethane were added dropwise and the medium reaction was stirred to room temperature for 24 hours. The reaction medium was washed three times times with a aqueous solution of hydrochloric acid 1 N. The organic phase was dried on sulfate anhydrous sodium, filtered and evaporated. The oil obtained was chromatographed on silica gel (800 g prepacked column) eluted with heptane / ethyl acetate (gradient).
4.03 g of (R) -1- (2-hydroxy-3-nitro-benzoyl) -pyrrolidine-2-carboxylate methyl have been obtained in the form of a yellow meringue. Yield = 67%
Step 7:
Methyl 1- (3-Amino-2-hydroxy-benzoyl) -pyrrolidine-2-carboxylate WO 2013/061004

38 A solution of 4.03 g (13.63 mmol, 1.0 eq) of (R) -1- (2-hydroxy-3-nitro-benzoy1) -methyl pyrrolidine-2-carboxylate in 50 mL of methanol was stirred under pressure atmospheric hydrogen in the presence of 390 mg (10% by mass) of palladium on charcoal at 10% for 3 days. The reaction medium was filtered on celite, rinsed with methanol and evaporated. The residue was chromatographed on silica gel (prepacked column 200 g) eluted at heptane / ethyl acetate (gradient). 2.65 g of (R) -1- (3-amino-2-hydroxy) benzoy1) -Methyl pyrrolidine-2-carboxylate was obtained as an oil yellow.
Yield = 74%.
Step 8:
(R) -1- [2-Hydroxy-3- (2-methoxy-3,4-dioxo-eyelobut-1-enylamino) -benzoyl] -pyrrolidine-2-methyl carboxylate A mixture of 2.64 g (10 mmol, 1 eq) of (R) -1- (3-amino-2-hydroxy-benzoyl) -pyrrolidine-2-methyl carboxylate and 2.84 g (20 mmol, 2.0 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 80 mL of ethanol was heated at 50 ° C for 4.5 hours. The residue has been taken up with ethyl acetate and washed three times with an aqueous solution of 1M sodium dihydrogenphosphate The organic phase was dried over sulfate Sodium anhydrous, filtered and evaporated. The oil was chromatographed on silica gel (column 300 g pre-packed) eluted with heptane / ethyl acetate (gradient). 1.27 g of (R) -1- [2-hydroxy-3- (2-Methoxy-3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate methyl were obtained as a white solid. Yield = 34%
Step 9:
(R) -1-P-Hydroxy-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methylf-aminol-Methyl 3,4-dioxo-eyelobut-1-enylamino) -benzoyll-pyrrolidine-2-carboxylate A mixture of 463 mg (1.24 mmol, 1 eq) of (R) -142-hydroxy-3- (2-methoxy-3,4-dioxo methyl cyclobut-1-enylamino) -benzoyll-pyrrolidine-2-carboxylate and 293 mg (1.48 mmol, 1.2 eq) of C - [(R) -C- (5-methyl-furan-2-yl) -C-tetrahydro-thiophen-2-yl) methylamine (diastereoisomer 2) in solution in 15 mL of methanol was heated to 50 ° C
during 14 hours. The reaction medium was evaporated and the residue was chromatographed on silica gel HP (puriFlash PF-15SI / 40G column, puriFlash) eluted with dichloromethane / acetate ethyl (Gradient). 538 mg of (R) -1- [2-hydroxy-3 - (2 - {[(5-methyl-furan-2-yl)}
(Tetrahydro-thiophen-2-yl) -methyl] -amino-3,4-dioxo-cyclohexyl-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate methyl were obtained as a yellow solid. Yield = 81%.

WO 2013/061004

39 1 H NMR (DMSO-d 6, 400 MHz): 1.82-1.99 (m, 5H), 2.03-2.05 (m, 2H), 2.26 (s, 3H), 2.75-2.84 (m, 2H), 3.59-3.67 (m, 2H), 3.84-3.88 (m, 1H), 3.89 (s, 3H), 4.53 (m, 1H), 5.19 (t, J =
9.6 Hz, 1H), 6.06 (dd, J = 1.0-3.0 Hz, 1H), 6.30 (d, J = 3.1 Hz, 1H), 6.92 (t, J = 9.6 Hz, 1H), 7.12 (d, J = 6.2 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 8.77 (d, J = 9.6 Hz, 1H), 9.38 (s, 1H).

Preparation of (S) -1-11-hydroxy-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-y1) -methyl-amino} -3,4-dioxo-cyclobut-l-enylamino) -benzoyll-pyrrolidine-2-carboxylate methyl Step 1 Step 2 Step 3 Step 4 s Step 5 S
SS ______ 0 ______________ Na __ NH Me00C ' HO
ON \ ON \ ON \ ON \

Step 1 diesteroisols 1 and 2 Step 9 HO- 0 ' Step 6 CN = Step C \ N NH,) Step 8 sir0 HN
HO NO, NOT
ISI 2 Me000 0 0H Me00C 0 OH

Me00C O 0H H 0¨
Steps 1 to 5:
In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) methylamine (diastereoisomers 1 and 2) were prepared.
Steps 6 to 9:
In a manner analogous to EXAMPLE 6 (Steps 6 to 9), and from the hydrochloride of the ester of L-proline and C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-y1) -methylamine (diastereoisomer 2), (S) -1- [2-hydroxy-3- (2 - {[(5-methyl-furan-2-y1) -(tetrahydro-thiophen-2-yl) -methyl-amino} -3,4-dioxo-cyclo-but-1-enylamino) -b enzo yl] -Methyl pyrrolidine-2-carboxylate was prepared. Yield = 11%.
1 H NMR (DMSO-d 6, 400 MHz): 1.84-1.93 (m, 4H), 2.01-2.04 (m, 2H), 2.26 (s, 3H), 2.29-2.33 (m, 1H), 2.79-2.82 (m, 2H), 3.35-3.42 (m, 1H), 3.61-3.65 (m, 2H), 3.67 (s, 3H), 3.95-3.97 (m, 1H), 4.56 (m, 1H), 5.40 (t, J = 8.0 Hz, 1H), 6.06 (d, J = 2.0 Hz, 1H), 6.26 (d, J = 2.9 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 7.12 (m, 1H), 7.85 (d, J = 7.6 Hz, 1H), 8.84 (d, J = 9.7 Hz, 1H), 9.54 (s, 1H).

WO 2013/061004

40 Steps 6 to 9:
In a manner analogous to EXAMPLE 6 (Steps 6 to 9), and from the hydrochloride of the ester of L-proline and C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-y1) -methylamine (diastereoisomer 1), (S) -1- [2-hydroxy-3 - (2- {[(5-methyl-furan-2-yl) -(Tetrahydro-thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobutyl enylamino) -b enzo yl] -Methyl pyrrolidine-2-carboxylate was prepared. Yield = 7%.
1 H NMR (DMSO-d 6, 400 MHz): 1.64-1.68 (m, 1H), 1.88-1.93 (m, 4H), 2.03-2.06 (m, 2H), 2.27 (s, 3H), 2.76-2.81 (m, 2H), 3.38 (m, 1H), 3.61-3.64 (m, 2H), 3.67 (s, 3H), 3.85 (m, 1H), 4.52 (m, 1H), 5.18 (t, J = 9.7 Hz, 1H), 6.06 (d, J = 2.2 Hz, 1H), 6.30 (d, J =
3.1 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.94 (t, 1H), 7.12 (m, 1H), 7.85 (m, 1H), 8.77 (d, J =
9.6 Hz, 1H), 9.38 (s, 1H).

Preparation of 2-hydroxy-N-methyl-3- (2 - {[(S) - (5-methyl-furan-2-yl) -tetrahydro]
thiophen-2-yl-methyl-amino-3,4-dioxo-cyclobut-1-enylamino) -N- (2,2,2 trifluoro-ethyl) -benzamide F
Ho_IEtape 1 Step 2 S Step 3 S
EtsPe 4 S Step 5 S
S-7 s 0 o OH
Na NH, No 0 Step 9 Step 1 diastereoisomers 1 and 2III

HO
Step 6 FF Step 7 FF, IF OS Step 8 if N ,,,, I = r HN

0 OH 0 OH 01.1 NH, ---Steps 1 to 5:
In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) methylamine (diastereoisomers 1 and 2) were prepared.
Steps 6 to 9:
In a manner analogous to EXAMPLE 6 (Steps 6 to 9), and from the hydrochloride of methyl (2,2,2-trifluoro-ethyl) -amine and C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-y1) -methylamine (diastereoisomer 2), 2-hydroxy-N-methyl-3- (2 - {[(S) - (5-methyl) furan-2-y1) -tetrahydro-thiophen-2-ylmethylamino} -3,4-dioxo-cyclobut-1-enylamino) N- (2,2,2 trifluoro-ethyl) -benzamide was prepared. Yield = 8%.

WO 2013/061004

41 1 H NMR (DMSO-d 6, 400 MHz): 1.83 (m, 1H), 1.91 (m, 1H), 2.06 (m, 2H), 2.27 (s, 3H), 2.80 (m, 2H), 2.96 (s, 2H), 3.08 (m, 1H), 3.87 (m, 1H), 4.34 (s, 1H), 5.20 (t, J = 9.6 Hz, 1H), 6.06 (d, J = 2.9 Hz, 1H), 6.30 (d, J = 3.0 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 8.73 (d, J = 9.6 Hz, 1H), 9.53 (s, 1H), 9.79 (s, 1H).
Steps 6 to 9:
In a manner analogous to EXAMPLE 6 (Steps 6 to 9), and from the hydrochloride of methyl (2,2,2-trifluoro-ethyl) -amine and C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-y1) -methylamine (diastereoisomer 1), (S) -1- [2-hydroxy-3- (2 - {[(5-methyl-furan-2-yl) -(Tetrahydro-thiophen-2-yl) -methyl-amino} -3,4-dioxo-cyclobut-1-enylamino) b enzo yl] -Methyl pyrrolidine-2-carboxylate was prepared. Yield = 10%.
1 H NMR (DMSO-d 6, 400 MHz): 1.65 (m, 1H), 1.89 (m, 1H), 2.02 (m, 2H), 2.26 (s, 3H), 2.80 (m, 2H), 2.97 (s, 3H), 4.01 (m, 1H), 4.34 (s, 1H), 5.41 (dd, J = 6.7 Hz, 9.4 Hz, 1H), 6.06 (d, J = 3.0 Hz, 1H), 6.26 (d, J = 3.0 Hz, 1H), 6.83 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 8.77 (d, J = 9.6 Hz, 1H), 9.52 (s, 1H), 9.81 (s, 1H).

Preparation of {11-hydroxy-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2 y1) -methyl-amino} -3,4-dioxo-cyclobut-l-enylamino) -benzoyll-methyl-amino-acetate of methyl s Step 1 s _.... Step 2 s 0 Step 3 S Step 4 S
Step 5 s MeOOCN
isat HO

ON \ ON \ ON \ \ 0 Step 9 hi0 Step 1 diastereoisomers 1 and 2 HN
HN

Step 6 Step 7 Step 8 0 HO
NO, ## STR1 ##

Steps 1 to 5:
In a similar manner to EXAMPLE 2 (steps 1 to 5), the diastereoisomers 1 and 2 of the C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) -methylamine were prepared.
Steps 6 to 9:

WO 2013/061004

42 In a similar manner to EXAMPLE 6 (steps 6 to 9), and from the methylamino acetate methyl and C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) methylamine (Diastereoiso mother 2), {[2-hydroxy-3 - (2 - {[(5-methyl-furan-2-yl)}
(tetrahydro-thiophen-2-yl) methyl] amino} -3,4-dioxo-cyclohexyl-1-enylamino) -benzoyl] -methyl-amino}
-acetate Methyl was prepared. Yield = 26%.
1 H NMR (DMSO-d 6, 400 MHz): 1.81-1.98 (m, 2H), 2.05 (m, 2H), 2.26 (s, 3H), 2.78-2.85 (m, 2H), 2.95 (s, 3H), 3.67 (s, 3H), 3.84-3.88 (m, 1H), 4.20 (m, 2H), 5.19 (m, 1H), 6.07 (d, J = 3.0 Hz, 1H), 6.30 (d, J = 3.0 Hz, 1H), 6.90 (m, 1H), 7.78 (m, 1H), 8.79 (d, 1H), 9.32 (s, 1H), 10.53 (s, 1H).
Steps 6 to 9:
In a similar manner to EXAMPLE 6 (steps 6 to 9), and from the methylamino acetate methyl and C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) methylamine (Diastereoiso mother 1), {[2-hydroxy-3 - (2 - {[(5-methyl-furan-2-yl) -(tetrahydro-thiophen-2-yl) methyl] -amino} -3,4-dioxo-cyclo-butyl-1-enylamino) -benzoyl] -methyl-aminoI
-acetate Methyl was prepared. Yield = 37%.
1 H NMR (DMSO-d 6, 400 MHz): 1.65 (m, 1H), 1.88-1.92 (m, 2H), 1.98-2.05 (m, 2H), 2.26 (s, 3H), 2.79-2.82 (m, 2H), 2.96 (s, 3H), 3.67 (s, 3H), 3.95-4.00 (m, 1H), 4.22 (m, 2H), 5.40 (dd, 1H), 6.05 (dd, J = 3.0 Hz, 1H), 6.26 (d, J = 3.0 Hz, 1H), 6.90 (m, 2H), 7.76 (m, 1H), 8.80 (d, 1H), 9.52 (s, 1H), 9.81 (s, 1H).

Preparation of 6-chloro-2-hydroxy-N, N-dimethyl-3- (2-11 (5-methyl-furan-2-yl) -(Tetrahydro-thiophen-2-y1) -methyl-amino-3,4-dioxo-cyclobut-1-enylamino) -benzenesulfonamide WO 2013/061004

43 s (+) NH, Step 1 (-) NH2 NI-12 NOT
diastereoisomer 2 enantiomer 1 enantiomer 2 at = a 0, k Step L Step 3 Step 4 N 1-12 N Step ., s N

"μOH H

=

Cl \ NN 0 NHH
c>"
Step 1:
C- (5-Methyl-furan-2-y1) C- (tetrahydro-thiophen-2-y1) methylamine The separation of diastereoisomer 2 (prepared in EXAMPLE 2) into enantiomers has been performed on chiral semi-preparative columns CHIRALPACKR AD-H 5 ium and CHIRALPACKR AZ-H 5 ium, mobile phase: hexane / ethanol (70/30), flow rate of 5 mL / min.
Enantiomer 1 (-) of diastereoisomer 2: 1st eluted Enantiomer 2 (+) of diastereoisomer 2: 2nd eluted 2nd step:
2-tert-butyl-6-chloro-benzooxazole-7-sulfonic acid dimethylamide 12.9 mL (93 mmol, 3.0 eq) of triethylamine and 93 mL of 2M dimethylamine in the tetrahydrofuran was added dropwise to a solution of 9.55 g (31 mmol, 1.0 eq) of 2-tert-butyl-6-chlorobenzoxazole-7-sulfonyl chloride in 200 mL of tetrahydrofuran cooled to 0 ° C. The reaction medium was stirred at 0 ° C.
during 3 hours then was treated with water. The reaction medium was extracted ethyl acetate. The organic phases were collected, washed with water, dried over magnesium, filtered and evaporated. 9.12 g of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonic dimethylamide were obtained as a beige solid. Yield = 93%.
Step 3:
3-A-6-chloro-2-hydroxy-N, N-dimethylbenzenesulfonamide 11 mL (205 mmol, 1.20 V) of sulfuric acid and 11 mL of water were added drip a solution of 9.12 g (28.8 mmol, 1.0 eq) of 2-tert-butyl-6-chloroacetic acid benzooxazole-7-sulfonic dimethylamide in 41 mL of 1,4-dioxane. The reaction medium been heated to WO 2013/061004

44 reflux for 6 hours and a half. The reaction medium was concentrated and 440 mL of soda 1N were added (pH at 8). The solution was extracted with ethyl acetate.
The phases organics were pooled, dried over magnesium sulphate, filtered and evaporated. 6.94 g of 3-amino-6-chloro-2-hydroxy-N, N-dimethylbenzenesulfonamide have been obtained under form of a brown solid. Yield = 96%
Step 4:
6-Chloro-3- (2-ethoxy-3,4-dioxo-cyclobut-l-enylamino) -2-hydroxy-N, N-dimethyl-benzenesulfonamide A mixture of 6.94 g (27.7 mmol, 1.0 eq) of 3-amino-6-chloro-2-hydroxy-N, N-dimethyl benzenesulfonamide and 9.42 g (55.4 mmol, 2.0 eq) of 3,4-diethoxy-3-cyclobutene-1,2-dione in 70 mL of ethanol was stirred at room temperature for 2 hours (4% of formed product). The reaction medium was heated at 50 ° C. for 5 days.
The insoluble has been filtered and dried under vacuum at 45 ° C. 7.67 g of 6-chloro-3- (2-ethoxy-3,4-dioxo) cyclobut-1-enylamino) -2-hydroxy-N, N-dimethyl-benzenesulfonamide were obtained under form of a yellow solid. Yield = 73%
Step 5:
(-) - 6-Chloro-2-hydroxy-N, N-diméthy1-3- (2 - {[(5-methyl-furan-2-y1) - (tetrahydro thiophen-2-y1) -methyli-amino-3,4-dioxo-cyclobut-the-enylamino) benzenesulfonamide A mixture of 500 mg (1.33 mmol, 1.0 eq) of 6-chloro-3- (2-ethoxy-3,4-dioxo) cyclobut-l-enylamino) -2-hydroxy-N, N-dimethyl-benzenesulfonamide and 316 mg (1.60 mmol;
1.2 eq) (-) - C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) -methylamine solution in 20 mL of methanol was heated at 50C for 16 hours. The insoluble has been filtered, washed with a little methanol and dried under vacuum at 45 C. 615 mg of (+ 6-chloro-2-hydroxy-N, N-dimethyl 3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl-amino} -3 , 4-dioxo-cyclobut-1 -enylamino) -benzenesulfonamide (diastereoisomer 1) were obtained under form of a off-white solid. Yield = 88%
1 H NMR (DMSO-d 6, 400 MHz): 1.81-1.98 (m, 2H), 2.05 (m, 2H), 2.27 (s, 3H), 2.75-.
2.85 (m, 2H), 2.87 (s, 6H), 3.17 (m, 2H), 3.84-3.90 (m, 1H), 4.10 (m, 1H), 5.19 (m, 1H), 6.07 (d, J =
3.0 Hz, 1H), 6.31 (d, J = 3.0 Hz, 1H), 7.20 (m, 1H), 8.02 (d, J = 12.0 Hz, 1H), 8.84 (d, 1H), 9.48 (s, 1H), 10.53 (s, 1H).
Step 5 bis:

WO 2013/061004

45 (+) - 6-Chloro-2-hydroxy-N, N-diméthy1-3- (2 - {[(5-methyl-furan-2-y1) - (tetrahydro thiophen-2-y1) -methylf-amino-3,4-dioxo-cyclobut-1-enylamino) -benzenesulfonamide A mixture of 500 mg (1.33 mmol, 1.0 eq) of 6-chloro-3- (2-ethoxy-3,4-dioxo) cyclobut-l-enylamino) -2-hydroxy-N, N-dimethyl-benzenesulfonamide and 316 mg (1.60 mmol;
1.2 eq) (+) - C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) -methylamine solution in 20 ml of methanol was heated at 50 ° C. for 16 hours. The insoluble has been filtered, washed with a little methanol and dried under vacuum at 45 ° C. 595 mg of (+) - 6-chloro-2-hydroxy-N, N-dimethyl-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyll) amino} -3, 4-dioxo cyclobut-1-enylamino) -benzenesulfonamide (diastereoisomer 2) have been obtained in form an off-white solid. Yield = 85%
1 H NMR (DMSO-d 6, 400 MHz): 1.81-1.98 (m, 2H), 2.05 (m, 2H), 2.27 (s, 3H), 2.75-.
2.85 (m, 2H), 2.87 (s, 6H), 3.17 (m, 2H), 3.84-3.90 (m, 1H), 4.10 (m, 1H), 5.19 (m, 1H), 6.07 (d, J =
3.0 Hz, 1H), 6.31 (d, J = 3.0 Hz, 1H), 7.20 (m, 1H), 8.02 (d, J = 12.0 Hz, 1H), 8.84 (d, 1H), 9.48 (s, 1H), 10.53 (s, 1H).

Preparation of 2-hydroxy-N, N-dimethyl-3- (2 - [(R) - (5-methyl-furan-2-yl) -tetrahydro furan-2-yl-methyll-amino] -3,4-dioxo-cyclobut-1-enylamino) -benzamide HO Step 1 0 Step 2 0 Step 3 Ho Step 4 Step 5 0 Step 6 -...- Ns \ NOT

'' -1 lir & N ar? :: \ ......
NOT

Step 1:
(R) -Tetrahydro-furan-2-methoxy-methyl-carboxamide To a solution of 10.0 g (86.1 mmol, 1.0 eq) of tetrahydrofuran-2-carboxylic in 50 ml of dichloromethane were added dropwise 8.0 ml (110.1 mmol;
1.28 eq) from thionyl chloride at room temperature in 15 minutes. The environment reaction was stirred to room temperature for 2 hours until there is no more gassing.
The dichloromethane and the excess of thionyl chloride were evaporated under empty and the residue has WO 2013/061004

46 was coevaporated three times with 50 mL of dichloromethane. Acid chloride got was solubilized in 50 mL of dichloromethane and 9.24 g (94.7 mmol, 1.10 eq) of hydrochloride N, O-dimethylhydroxylamine was added. The reaction medium was cooled to 0 C and a mixture of 27.5 mL (207.0 mol, 2.40 eq) of triethylamine in 50 mL of dichloromethane a added in 90 minutes (keeping the temperature in below 5 C). After the addition, the reaction medium was stirred at room temperature ambient during a hour and then washed with 250 ml of an aqueous solution of hydrochloric acid at 1M. The aqueous phase was extracted with 50 mL dichloromethane. Organic phases have been pooled, washed with 50 mL of an aqueous solution of hydrogen phosphate sodium saturated, dried over anhydrous magnesium sulphate, filtered and evaporated. 8.5 g of (R) -Tetrahydro-furan-2-methoxy-methyl-carboxamide was obtained in the form of an oil.
Yield = 62%.
2nd step:
(5-Methyl-furan-2-y1) - (R) -tetrahydro-furan-2-yl-methanone 87 mL (215.6 mmol, 1.50 eq) of 2.5 M n-butyllithium in hexane were added drop to drop on a solution of 19.5 mL (215.6 mmol, 1.50 eq) of 2-methyl furan in 550 mL
of tetrahydrofuran cooled to -78 C. The mixture was allowed to rise to temperature room temperature for 2 hours and then cooled to -78 C. A solution of 22.88 g (143.7 mmol;
1.00 eq) of (R) -tetrahydro-furan-2-methoxy-methyl-carboxamide in 200 mL of tetrahydrofuran was added and the reaction mixture was left at 0 C for 2 hours. The reaction medium was diluted with 200 mL of ethyl acetate and washed with 300 mL of a 1N aqueous hydrochloric acid solution. The aqueous phase has been separate and extracted with 200 mL of ethyl acetate. The organic phases have been collected, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium, filtered and evaporated. The brown oil obtained was filtered on silica (eluent : Heptane / Acetate 90/10 ethyl). 17.72 g of (5-methyl-furan-2-yl) - (R) -tetrahydro-furan-2-yl methanone have been obtained. Yield = 68%.
Step 3:
(5-Methyl-furan-2-y1) - (R) -tetrahydro-furan-2-yl-methanol 2.27 g (59.9 mmol, 1.20 eq) of sodium borohydride were added by small portions on a solution of 9.00 g (49.9 mmol, 1.0 eq) of (5-methyl-furan-2-yl) - (R) -tetrahydro-furan-2-yl-methanone in 100 mL of tetrahydrofuran cooled to 0 C. The medium reaction was WO 2013/061004

47 stirred at room temperature for 3 hours. The reaction medium was poured into 200 mL
of ethyl acetate and then 100 ml of water were added. The aqueous phase has been extracted at ethyl acetate and then the organic phases were collected, washed with a solution of saturated sodium chloride, dried over anhydrous magnesium sulphate, filtered and evaporated.
8.10 g of (5-methyl-furan-2-yl) - (R) -tetrahydro-furan-2-yl-methanol were added.
obtained.
Yield = 92%.
Step 4:
2 - ((R) -azido-tetrahydro-furan-2-yl-methyl) -5-methyl-furan To a solution of 8.40 g (46.1 mmol, 1.0 eq) of (5-methyl-furan-2-yl) - (R) -tetrahydrofuran-2-γ-methanol in 300 mL of toluene cooled to 0 ° C was added 11.9 mL
(55.3 mmol;
1.2 eq) of diphenylphosphoryl azide then 8.3 mL (55.3 mmol, 1.2 eq) of 1.8-diazabicyclo [5.4.0] undec-7-ene dropwise. The mixture was left return to temperature gently and then stirred for 24 hours. The reaction medium been treated at water and extracted with ethyl acetate. The organic phases have been collected, washed with a 1M sodium dihydrogenphosphate solution, dried over sodium sulphate magnesium, filtered and evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI / 300G, puriFlash) eluted with heptane / ethyl acetate (90/10). 6.0 g of 24 (R) -azido-tetrahydro-furan-2-yl-methyl) -5-methyl-furan were obtained (mixture of 2 diastereoisomers). Yield = 63%.
Step 5:
C - [(R) -C- (5-Methyl-furan-2-y1) -C-tetrahydro-furan-2-y1J-methylamine A solution of 6.00 g (29.0 mmol, 1.0 eq) of 24 (R) -azido-tetrahydro-furan-2-yl-methyl) -5-methyl furan in 250 ml of methanol and in the presence of 600 mg (10% by weight) from Pd / C
10% was stirred at room temperature under atmospheric pressure of hydrogen for 5 days. The reaction mixture was filtered on celite and the filtrate was evaporated. The residue was chromatographed on silica gel (puriFlash IR-50S1-STD / 300G column, puriFlash) eluted at dichloromethane / ethyl acetate (gradient). 4.6 g of C - [(R) -C- (5-methyl-furan) 2-y1) -C-tetrahydro-furan-2-yl] -methylamine were obtained (mixture of 2 diastereoisomers).
Yield = 70%.
Step 6:

WO 2013/061004

48 2-Hydroxy-N, N-diméthy1-3- (2 - {[(R) - (5-methyl-furan-2-y1) -tetrahydro-furan-2-yl-méthylf--amino-3,4-dioxo-cyclobut-1-enylamino) benzamide A mixture of 4.5 g (14.7 mmol, 1.0 eq) of 3- (2-ethoxy-3,4-dioxo-cyclobut-1) enylamino) -2-hydroxy-N, N-dimethylbenzamide and 2.7 g (14.7 mmol; 1.0 eq) of C - [(R) -C- (5-methyl furan-2-yl) -C-tetrahydro-furan-2-yl] methylamine dissolved in 100 ml of methanol has been stirred at 50 ° C overnight. The reaction medium was evaporated and purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate 70/30) and has been recrystallized from Heptane / Dichloromethane (75/25). 5.6 g of 2-hydroxy-N, N-dimethyl-3- (2- {[(R) - (5-methyl-furan-2-yl) -tetrahydro-furan-2-yl-methyl) amino} -3, 4-dioxo cyclobut-1-enylamino) -benzamide have been obtained. Yield = 54%.
1 H NMR (DMSO-d 6, 400 MHz): 1.75-1.80 (m, 2H), 1.80-1.87 (m, 1H), 1.88-2.02 m, 1H), 2.27 (d, J = 1.8 Hz, 3H), 2.94 (s, 6H), 3.65-3.75 (m, 2H), 4.24-4.26 (m, 1H), 5.32 (dd, J1 = 9.2 Hz, J2 = 5.6 Hz, 1H), 6.06 (dd, J1 = 1.0 Hz, J2 = 3.0 Hz, 1H), 6.28 (d, J =
3.1 Hz, 1H), 6.87 (m, 2H), 7.77 (m, 1H), 8.84 (m, 1H), 9.45 (s, 1H), 9.95 (s, 1H).

Preparation of 2-hydroxy-N, N-dimethyl-3- (2 - {[(S) - (5-methyl-furan-2-yl) -tetrahydro furan-2-yl-methyll-amino] -3,4-dioxo-cyclobut-1-enylarnino) -benzamide \NOT
110 he NOT
. . . . 0 HN

In a similar manner to EXAMPLE 11 (Steps 1 to 6), 2-hydroxy-N, N-dimethyl-3- (2-{[(S) -(5-Methyl-furan-2-yl) -tetrahydro-furan-2-yl-methyl] -amino} -3,4-dioxo cyc lo but-1-enylamino) -benzamide has been prepared:
1 H NMR (DMSO-d 6, 400 MHz): 1.50-1.80 (m, 2H); 1.84 (m, 1H); 1.98 (m, 1H);
2.27 (s, 3H); 2.93 (s, 6H); 3.60-3.80 (m, 2H); 4.24 (m, 1H); 5.20-5.40 (m, 1H);
6.05 (d, J = 2.0 Hz, 1H); 6.28 (d, J = 3.0 Hz, 1H), 6.87 (m, 2H); 7.77 (m, 1H); 8.81 (d, J = 9.6 Hz, 1H), 9.46 (s, 1H), 9.97 (s, 1H).

WO 2013/061004

49 Preparation of 3- (3,4-dioxo-2 - {[phenyktétrahydrofuran-2-y1) -methyl-aminol-cyclobut-1-enyl-amino) -2-hydroxy-N, N-dimethyl-benzamide o o 'NY' i laughed.

In a similar manner to EXAMPLE 1 (steps 6 to 9), and from C-phenyl-C-(tetrahydrofuran-2-yl) methylamine and 3- (2-methoxy-3,4-dioxo) cyclobut-1-enylamino) -2-hydroxy-N, N-dimethylbenzamide, 3- (3,4-dioxo-2-yl) phenyl-(Tetrahydrofuran 2-yl) -methyl] -amino-cyclobut-1-enylamino) -2-hydroxy-N, N-dimethyl-b-enzamide has been prepare. (mixture of diastereoisomers) (mp = 120-125 ° C.). LC / MS: 99.66%
[435].
1 H NMR (DMSO-d 6, 400 MHz): 1.57-1.91 (m, 5H); 2.94 (s, 6H); 3.64-3.73 (m, 2H); 3.84-3.93 (m, 1H); 4.19-4.28 (m, 1H); 5.27 (t, 1H); 6.85 (d, J = 6.2 Hz, 2H), 7.3-7.42 (m, 6H);
7.73 (dd, J = 8.1 Hz, 1H); 8.86-8.96 (dd, J = 9.6 Hz, 1H).

Preparation of 342-{[((R) -2,2-dimethyl- [1,31dioxolan-4-yl] - (5-methyl-furan-2-yl) -Methyl-amino] -3,4-dioxo-cyclobut-1-enylamino) -2-hydroxy-N, N-dimethyl-benzamide (diastereoisomers 1 and 2) NH, 0 0 +. ij - "

In a similar manner to EXAMPLE 1 (steps 3 to 5), and from (S) -glyceraldehyde acetonide, C - ((R) -2,2-dimethyl- [1,3] dioxolan-4-yl) -C- (5-methyl-furan-2-yl) -methylamine a been prepared. Yield = 10%.

WO 2013/061004

50 The separation of the 2 diastereoisomers was carried out at the level of the azide intermediate (2e ' step described below).
(R) -4- [Azido- (5-methyl-furan-2-yl) -methyl-2,2-dimethyl- [1,31] dioxolane 4.15 g (15.0 mmol, 1.2 eq) of diphenylphosphoryl azide was added dropwise drop on a solution of 2.67 g (12.5 mmol, 1 eq) of ((S) -2,2-dimethyl- [1,3] dioxolan-4-y1) - (5-methyl-crude furan-2-yl) -methanol in 40 mL of toluene. The reaction medium was cooled to 0 C
then 2.2 mL (15.0 mmol, 1.2 eq) of 1,8-diazabicyclo [5.4.0] undec-7-ene were added drop by drop. The reaction medium was stirred at ambient temperature for 42 hours.
hours. The reaction medium (heterogeneous) was decanted, treated with water and extracted ethyl acetate. The organic phases were collected, washed with a solution of dihydrogen phosphate 1N sodium, dried over magnesium sulphate, filtered and evaporated. The residue has been chromatographed on silica gel (puriFlash IR-50SI / 200G column, Spot II
then column RediSep Rf Gold 40g, Spot II) eluted with heptane / ethyl acetate (95/5).
562 mg of (R) -4- [azido - (5-methyl-furan-2-yl) methyl] -2,2-dimethyl- [1,3] dioxo lane (diastereoisomer 1) were obtained.
257 mg of (R) -4- [azido- (5-methyl-furan-2-yl) -methyl] -2,2-dimethyl-[1,3] dioxolane (diastereoisomer 2) were obtained.
In a similar way to EXAMPLE 1 (steps 6 to 9), and from the 2 diastereoisomers C-(R) -2,2-dimethyl- [1,3] dioxolan-4-yl) -C- (5-methyl-furan-2-yl) methylamine and 3- (2-ethoxy-3,4-dioxo-cyclobut-1-enylamino) -2-hydroxy-N, N-dimethyl-benzamide, the diastereoisomers 1 and 2 of 3- (2 - {[((R) -2,2-dimethyl- [1,3] dioxolan-4-yl) - (5-methyl-furan-2-yl) -methyl-amino] -3,4-dioxo-cyclohexyl-1-enylamino) -2-hydroxy-N, N-dimethyl-enzamide have been prepared. Yield of 78% (diastereoisomer 1) and 52%
(diastereoisomer 2).
3- (2- {k (R) -2,2-dimethyl- [1,31dioxolan-4-y1) - (5-methyl-furan-2-y1) -méthylf--amino-3,4 dioxo-eyelobut-1-enylamino) -2-hydroxy-N, N-dimethylbenzamide (diastereoisomer 1).
1 H NMR (DMSO-d 6, 400 MHz): 1.27 (s, 3H); 1.29 (s, 3H); 2.27 (s, 3H); 2.94 (s, 6H); 3.86 (m, 1H); 4.14 (m, 1H); 4.49 (q, J = 5.9 Hz, 1H); 5.43 (dd, J = 9.4 Hz, 1H) ; 6.06 (dd, J = 3.0 Hz, 1H), 6.30 (d, J = 3.1 Hz, 1H); 6.87 (dd, J = 6.8 Hz, 2H); 7.76 (dd, J =
6.7 Hz, 1H); 8.82 (d, J = 9.6 Hz, 1H); 9.40 (s, 1H).
3- (2- {k (R) -2,2-dimethyl- [1,31dioxolan-4-y1) - (5-methyl-furan-2-y1) -méthylf--amino-3,4 dioxo-eyelobut-1-enylamino) -2-hydroxy-N, N-dimethylbenzamide (diastereoisomer Two).

WO 2013/061004

51 1 H NMR (DMSO-d 6, 400 MHz): 1.30 (s, 3H); 1.36 (s, 3H); 2.27 (s, 3H); 2.93 (s, 6H); 3.67 (q, J = 5.5 Hz, 1H); 4.06 (q, J = 6.8 Hz, 1H); 4.51 (q, J = 6.6 Hz, 1H);
5.32 (dd, J = 9.3 Hz, 1H); 6.07 (dd, J = 3.0 Hz, 1H), 6.35 (d, J = 3.1 Hz, 1H); 6.87 (m, 2H);
7.76 (dd, J = 7.1 Hz, 1H); 8.76 (d, J = 9.5 Hz, 1H); 9.40 (s, 1H); 9.92 (s, 1H).

Preparation of (S) -1-11-Fluoro-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-y1) -methyl-amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyll-pyrrolidine-2-carboxylate methyl o 0 IO Mr IE
NOT
HNH
0 0 F Fi In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 1) was prepared.
In a manner analogous to EXAMPLE 2 (Steps 6 to 9), and from the hydrochloride of the ester L-proline methyl, (S) -1- [2-fluoro-3- (2 - {[(5-methyl-furan-2-yl) -(tetrahydro-thiophen-2-yl) -methyl-amino} -3,4-dioxo-cyclobutyl-1-enylamino) -benzoyl] -Pyrro lidine-2-Methyl carboxylate was prepared.
1 H NMR (DMSO-d 6, 400 MHz): 1.66 (m, 1H), 1.85-2.05 (2m, 6H), 2.26 (s, 3H), 2.30 (m, 1H), 2.80-2.83 (m, 2H), 3.35-3.38 (m, 2H), 3.46-3.68 (2s, 3H), 4.02 (m, 1H), 4.32-4.53 (2m, 1H), 5.40 (t, J = 9.0 Hz, 1H), 6.06 (d, J = 3.0 Hz, 1H), 6.28 (d, J = 3.0 Hz, 1H), 7.02 (t, J = 6.2 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 8.05 (t, J = 8.1 Hz, 1H), 8.63 (d, J = 9.6).
Hz, 1H), 9.83 (s, 1H).

WO 2013/061004

52 PCT / FR2012 / 052478 Preparation of 3- (2-hydroxy-pyridin-3-ylamino) -4 - {[(5-methyl-furan-2-yl) -(tetrahydro-thiophen-2-y1) -methyl-amino-cyclobut-3-ene-1,2-dione 0 0 Chiral Step 1 0 Step 2 0 NINH2 -I "N /
N / he OH
OH OH H
/
In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) was prepared.
Step 1 :
3-Ethoxy-4- (2-hydroxy-pyridin-3-ylamino) -cyclobut-3-ene-1,2-dione A mixture of 1.82 g (16.5 mmol, lq) of 3-amino-pyridin-2-ol and 3.6 ml (24.8 mmol, 1.5 eq) 3,4-diethoxy-cyclobut-3-ene-1,2-dione (3.6 ml, 24.8 mmol) in solution in 87 ml of ethanol was stirred at room temperature for 16 hours and then heated to 50 C for 3 days with formation of a precipitate. Ethanol was added to to encourage the fall of precipitate which was filtered, washed with diethyl ether and dried under vacuum at 45 ° C.
C. 3.47 g of 3-Ethoxy-4- (2-hydroxy-pyridin-3-ylamino) -cyclobut-3-ene-1,2-dione have been obtained under form of a brown solid. Yield = 90%
2nd step:
3- (2-Hydroxy-pyridin-3-ylamino) -4 - {[(5-methyl-furan-2-y1) - (tetrahydro-thiophen 2-y1) -méthylf-amino-cyclobut-3-ene-1,2-dione A mixture of 500 mg (2.1 mmol, 1.0 eq) of 3-ethoxy-4- (2-hydroxy-pyridin-3-ylamino) -cyclobut-3-ene-1,2-dione and 505 mg (2.6 mmol, 1.2 eq) of C - [(R) -C- (5-methyl) furan-2-y1) -C-Tetrahydro-furan-2-yl] methylamine dissolved in 20 ml of methanol was heated to 50 C for 18 hours. The reaction medium was evaporated and the residue was chromatographed on silica gel with solid deposit (column puriFlash PF-15If / 40G
puriFlash) eluted with dichloromethane / methanol (gradient). The solid has been taken with a little of diethyl ether, filtered and dried under vacuum at 45 ° C. 610 mg of 3- (2-hydroxy) pyridin-3-ylamino) -4 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl-amino}
-cyclo but-3 -ene-1,2-dione were obtained as an off-white solid. Yield =
74%.
1H NMR (DMSO-d6, 400MHz): 1.79-1.84 (m, 1H), 1.88-1.92 (m, 1H), 2.00-2.06 (m, 2H), 2.26 (s, 3H), 2.75-2.83 (m, 2H), 3.81-3.86 (m, 1H), 5.17 (t, 1H), 6.05 (d, J =
2.1 Hz, 1H), WO 2013/061004

53 6.23-6.28 (m, 2H), 7.08 (dd, J = 6.5-1.5 Hz, 1H), 8.01 (dd, J = 7.3-1.5 Hz, 1H), 9.00 (d, 1H), 9.53 (s, 1H), 11.98 (s, 1H) Preparation of 3-1 [(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyll) -amino-4-(1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino) -cyclobut-3-ene-1,2-dione 0 Chiral Step 1 o Step 2 II Ni -, NN
r-2 NH
NH

In a similar manner to EXAMPLE 2 (Steps 1-5), C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) -methylamine (diastereoisomer 2) was prepared.
Step 1:
3-Methoxy-4- (1-méthy1-2-oxo-1,2-dihydro-pyridin-3-ylamino) -cyclobut-3-ene-1,2 dione In a manner analogous to EXAMPLE 16, (step 1), and from 3,4-dimethoxy-cyclobut-3-ene-1,2-dione, 3-methoxy-4- (1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) ylamino) -cyclobut-3 -ene-1,2-dione was prepared. Yield = 50%.
2nd step:
3 - {[(5-methyl-furan-2-y1) - (tetrahydro-thiophen-2-y1) -méthylf-amino-4- (1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino) -cyclobut-3-ene-1,2-dione In a similar manner to EXAMPLE 16, (step 2), 3 - {[(5-methyl-furan-2-yl) -(tetrahydro-thiophen-2-yl) -methyl-amino} -4- (1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl) ylamino) -cyc lo but-3-ene-1,2-dione was prepared. Yield = 90%.
1 H NMR (DMSO-d 6, 400 MHz): 1.77-1.84 (m, 1H), 1.86-1.94 (m, 1H), 1.98-2.08 (m, 2H), 2.26 (s, 3H), 2.73-2.85 (m, 2H), 3.52 (s, 3H), 3.82-3.88 (m, 1H), 5.18 (t, J =
9.5 Hz, 1H), 6.05-6.07 (m, 1H), 6.25-6.30 (m, 2H), 7.40 (dd, J = 6.8 Hz, J = 1.6 Hz, 1H), 7.99 (dd, J = 7.4 Hz, J = 1.6 Hz, 1H), 9.02 (d, J = 9.6 Hz, 1H), 9.57 (s, 1H) WO 2013/061004

54 Preparation of (-) - 2-hydroxy-N-methyl-3- (2 - {[(S) - (5-methyl-furan-2-yl) -(tetrahydro-thiophen-2-yl) -methyl-amino] -3,4-dioxo-cyclobut-1-enylamino) -N- (2,2,2-trifluoro-ethyl) -benzamide e 0 F - F NI

H
H
In a similar manner to EXAMPLE 10 (steps 1), (-) - C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) methylamine (enantiomer 1) was prepared.
In a similar manner to EXAMPLE 8 (steps 6 to 9), and from (-) - C- (5-methyl-furan-2-y1) -C- (tetrahydro-thiophen-2-yl) -methylamine (enantiomer 1), (+ 2-hydroxy-N-méthy1-3- (2-{[(S) - (5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -3, 4-dioxo-cyclobut-1 -enylamino) -N- (2,2,2-trifluoro-ethyl) -benzamide was prepared. Yield =
22%.
1 H NMR (DMSO-d 6, 400 MHz): 1.91 (m, 1H), 1.96 (m, 1H), 2.05 (m, 1H), 2.27 (s, 3H), 2.81 (m, 2H), 2.96 (s, 3H), 3.86 (m, 1H), 4.11 (m, 1H), 4.33 (s, 1H), 5.20 (t, J = 9.6 Hz, 1H), 6.06 (dd, J = 0.9 Hz, 3.0 Hz, 1H), 6.30 (d, J = 3.1 Hz, 1H), 6.82 (d, J = 6.5 Hz, 1H), 6.92 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 8.72 (d, J = 9.2 Hz, 1H), 9.34 (s, 1H), 9.79.
(s, 1H) Preparation of (-) - {11-hydroxy-3- (2 - {[(S) - (5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-yl) -methyl-amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyll-methyl-aminol acetate of methyl s NOT

HNH
H

In a similar manner to EXAMPLE 10 (steps 1), (-) - C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) methylamine (enantiomer 1) was prepared.

WO 2013/061004

55 In a similar manner to EXAMPLE 6 (Steps 6 to 9), and from methylamino-acetate of methyl and (-) - C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) -methylamine (Enantiomer 1), (-) - {[2-hydroxy-3- (2 - {[(S) - (5-methyl-furan-2-yl) -(Tetrahydro-thiophen-2-y1) -methyl-amino} -3,4-dioxo-cyclobut-l-enylamino) -benzoyll-methyl-amino} -acetate of Methyl was prepared. Yield = 25%.
1 H NMR (DMSO-d 6, 400 MHz): 1.80-1.96 (m, 2H), 1.99-2.10 (m, 2H), 2.37 (s, 3H), 2.74-2.85 (m, 2H), 2.95 (ss, 3H), 3.67 (ss, 3H), 3.83-3.89 (m, 1H), 4.00-4.35 (m, 2H), 5.20 (t, J =
9.6 Hz, 1H), 6.05-6.07 (m, 1H), 6.30 (d, J = 3.1 Hz, 1H), 6.65-6.95 (m, 2H), 7.80 (d, J = 7.8 Hz, 1H), 8.77 (d, J = 9.6 Hz, 1H), 9.36 (m, 1H), 9.82 (m, 1H) Preparation of (-) - 1-12-hydroxy-3- (2 - {[((S) -5-methyl-furan-2-yl) - (tetrahydro) thiophen 2-y1) -methyl-amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyll-pyrrolidine-2-(R) -methyl carboxylate chiral NHO
s NOT
H
0 \ o 0 OH H
In a similar manner to EXAMPLE 10 (steps 1), (-) - C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) methylamine (enantiomer 1) was prepared.
In a similar manner to EXAMPLE 6 (Steps 6 to 9), and from the ester methyl from L-proline and (-) - C- (5-methyl-furan-2-yl) -C- (tetrahydro-thiophen-2-yl) -methylamine (Enantiomer 1), (-) - 1- [2-hydroxy-3- (2- {R (S) -5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-y1) -methyl-amino} -3,4-dioxo-cyclobut-l-enylamino) -benzoy1] -pyrrolidine-2 (R) -carboxylate Methyl was prepared. Yield = 7%.
1 H NMR (DMSO-d 6, 400 MHz): 1.87-1.97 (m, 5H), 1.99-2.10 (m, 2H), 2.21-2.33.
(m, 4H), 2.73-2.85 (m, 2H), 3.56-3.70 (m, 5H), 3.83-3.89 (m, 1H), 4.50-4.60 (m, 1H), 5.20 (t, J = 9.6 Hz, 1H), 6.05-6.07 (m, 1H), 6.30 (d, J = 3.1 Hz, 1H), 6.91 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 8.78 (d, J = 9.5 Hz, 1H), 9.37 (m, 1H), 10.98 (m, 1H).

WO 2013/061004

56 Preparation of (-) - 6-chloro-2-hydroxy-N, N-dimethyl-3- (2-11 ((S) -5-methyl-furan 2-y1) -(tetrahydro-thiophen-2-yl) -methyl-amino-3,4-dioxo-cyclobut-1-enylamino) benzamide CI CI CI
Step 1 r iv gbi Step 2 riv gOl Step 3 _ ..
HO is 7 NO2 0 to 0 c, 0 o ICI CI
gbi 0 N IN Step 4 _, ... iI \ J = N * oQs VV
HHM F-b10 0 OH 0 ---- \

/ y In a similar manner to EXAMPLE 10 (steps 1), (-) - C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) methylamine (enantiomer 1) was prepared.
Step 1:
2,6-dichloro-N, N-diméthy1-3-nitro-benzamide A solution of 10.0 g (42.4 mmol, lq) of 2,6-dichloro-3-nitrobenzoic acid in 50 ml of Thionyl chloride was refluxed for 2 hours. The environment reaction was concentrated and coevaporated with toluene. The residue was taken up in 35 ml of tetrahydrofuran and then 48 ml of dimethylamine solution in the tetrahydrofuran been added drop by drop. After stirring for 20 minutes at room temperature ambient, water has has been added as well as ethyl acetate. The organic phase was washed at water, dried on anhydrous sodium sulphate, filtered and concentrated. 11.36 g of 2,6-dichloro-N, N-diméthy1-3-nitro-benzamide were obtained as a yellow oil. yield quantitative.
2nd step:
6-chloro-2-hydroxy-N, N-dimethyl-3-nitro-benzamide To a suspension of 7.16 g (179.01 mmol, 4.3 eq) of sodium hydride in 250 ml of tetrahydrofuran cooled to 0 C were added 3.2 ml (177.6 mmol, 4.2 eq) of water and 11.04 g WO 2013/061004

57 (41.96 mmol, 1.0 eq) 2,6-dichloro-N, N-dimethyl-3-nitro-benzamide (41.96).
mmol; 1.00 eq.) in solution in 130.00 ml of tetrahydrofuran. After 10 minutes, the reaction medium was stirred at room temperature for 19 hours. The reaction medium been hydrolyzed with an aqueous solution of 1N hydrochloric acid and extracted with acetate ethyl. The sentence organic material was washed with a 1N aqueous solution of hydrochloric acid, dried over sulphate anhydrous sodium, filtered and concentrated. The residue (11.82 g) was chromatographed on gel silica (prepacked column of 300 g, heptane / ethyl acetate eluent, from 40 to 80% acetate ethyl, 150 ml / min). 6.10 g of 6-chloro-2-hydroxy-N, N-dimethyl-3-nitro-benzamide have been obtained in the form of a yellow solid. Yield = 59%
Step 3:
6-Chloro-3- (2-ethoxy-3,4-dioxo-cyclobut-1-enylamino) -2-hydroxy-N, N-dimethyl-benzamide A solution of 5.96 g (24.4 mmol, 1 eq) of 6-chloro-2-hydroxy-N, N-dimethyl-3-nitro benzamide in 100 ml of methanol in the presence of 0.58 g of platinum oxide hydrated a was stirred under atmospheric pressure of hydrogen for 3 hours. The environment reaction filtered on celite and the filtrate was concentrated. The solution obtained was added drop by drop on 8.0 g (48.8 mmol, 2 eq) of 3,4-diethoxy-3-cyclobutene-1.2-dione in solution in 50 mL
of methanol. The reaction medium was stirred at ambient temperature for 18 hours. The The solvent was evaporated and the residue was chromatographed on silica gel.
(prepacked column 300 g, eluent heptane / acetone, 50 to 100% acetone). 4.42 g of 6-chloro 3- (2-ethoxy-3,4-dioxo-cyclobut-1-enylamino) -2-hydroxy-N, N-dimethyl-benzamide have been obtained under shape of a beige solid. Yield = 54%
Step 4:
(-) - 6-Chloro-2-hydroxy-N, N-diméthy1-3- (2-1 [((S) -5-methyl-furan-2-y1) -(tetrahydro-thiophen-2-y1) -méthylFamino} -3,4-dioxo-cyclobut-1-enylamino) benzamide A mixture of 560 mg (2.83 mmol, 1.2 eq) of (-) - C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) methylamine (enantiomer 1, prepared in EXAMPLE 10, step 1) and 800 mg (2.36 mmol, 1 eq) of 6-chloro-3- (2-ethoxy-3,4-dioxo-cyclobut-1-enylamino) -2-hydroxy N, N-dimethylbenzamide in 50 mL of methanol was heated at 50 ° C for 23 minutes.
hours.
The methanol was evaporated and the residue was taken up with ethyl acetate and washed with an aqueous solution of 1M sodium dihydrogenphosphate. The sentence organic was dried over anhydrous sodium sulphate, filtered and concentrated. The residue (0.90 g) has been WO 2013/061004

58 PCT / FR2012 / 052478 chromatographed on silica gel (prepacked column of 120 g, eluent dichloromethane / methanol, 0 to 10% methanol. 530 mg of (-) - 6-Chloro-2-hydroxy-N, N-dimethyl-3- (2- (R (S) -5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyll;
amino} -3.4-dioxo-cyclobut-1-enylamino) -benzamide were obtained in the form of a solid Brown.
Yield = 45%. Tf = 153-154C.
1 H NMR (DMSO-d 6, 400 MHz): 1.75-1.95 (m, 2H), 2.00-2.10 (m, 2H), 2.26 (s, 3H), 2.73-2.85 (m, 5H), 3.00 (s, 1H), 3.75-3.90 (m, 1H), 5.15-5.22 (m, 1H), 6.05 (s, 1H), 6.27-6.30 (m, 1H), 6.98 (dl, J = 8.5 Hz, 1H), 7.73-7.77 (m, 1H), 8.73-8.78 (m, 1H), 9.37 (m, 1H), 9.90-10.30 (m, 1H).

Preparation of (-) - 3-1-4-chloro-2-hydroxy-3- (4-methyl-piperazine) 1-sulfony1) -phénylamino1-4- {1 (5-methyl-furan-2-y1) - (tetrahydro-thiophen-2-y1) -méthyll-aminol-cyclobut-3-ene-L2-dione this this 0 .. Step 1 where, Step 2 Step 3 Step 3 s = N - "" N 0 /
Oj Cl / sO C
μμ, _, u OH NH2 ) CI Cl ar 0 Step 4 s = N
NOT
0 '.0 OH OH H 0 0 0 HNH
H /

In a similar manner to EXAMPLE 10 (steps 1), (-) - C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) methylamine (enantiomer 1) was prepared.
Step 1 :
2-tert-Buty1-6-chloro-7- (4-methyl-piperazin-1-sulfony1) -benzooxazol 1.62 ml (11.68 mmol, 1.2 eq) of triethylamine followed by 1.20 ml (10.71 mmol;
1.1 eq) 1-methylpiperazine was added to a solution of 3.0 g (9.73 mmol;
1.0 eq) of 2-tert-butyl-6-chloro-benzoxazole-7-sulfonyl chloride (commercial?) in 45 ml of tetrahydrofuran. The reaction medium was stirred at room temperature during 2 hours.
Water was added and the reaction medium was extracted with acetate ethyl. The phases WO 2013/061004

59 organics were pooled, dried over magnesium sulphate, filtered and evaporated. 3.57 g of 2-tert-butyl-6-chloro-7- (4-methyl-piperazin-1-sulfonyl) -benzooxazole were obtained under form of a brown sticky foam. Yield = 98%
2nd step :
6-Amino-3-chloro-2- (4-methyl-piperazine-1-sulfony1) -phenol 4.27 ml (0.08 mol, 1.20 V) of sulfuric acid diluted in 4.3 ml of water were added drop to drop on 3.56 g of 2-tert-butyl-6-chloro-7- (4-methyl-piperazine-1-sulfonyl) -benzooxazole (0.01 mol, 1.0 eq) in solution in 15 ml of 1,4-dioxane. The environment reaction was refluxed for six and a half hours. The reaction medium was concentrated and 1N sodium hydroxide was added (up to pH 7). The solution was extracted dichloromethane. The organic phases were collected, dried over magnesium sulphate, filtered and evaporated. The residue obtained was chromatographed on silica gel, eluent acetate of ethyl / dichloromethane 95/5. 2.0 g of 6-amino-3-chloro-2- (4-methyl) piperazine-1-sulfonylphenol were obtained as a thick brown oil.
Yield = 68%.
Step 3:
344-Chloro-2-hydroxy-3- (4-methyl-piperazine-1-sulfony1) -phenylamino] -4-ethoxy-cyclobut-3-ene-1,2-dione A mixture of 1.98 g (6.5 mmol, 1 eq) of 6-amino-3-chloro-2- (4-methyl) piperazine-1-sulfonylphenol and 2.20 g (48.8 mmol, 2 eq) of 3,4-diethoxy-3-cyclobutene-1.2-dione has dissolved in 20 mL of ethanol. The reaction medium was heated at 50 C during 16 hours. The insoluble material was filtered, washed with ethanol and dried under vacuum at 45.degree.
C. 2.05 g of 3- [4-chloro-2-hydroxy-3- (4-methyl-piperazin-1-sulfonyl) -phenylamino] -4-ethoxy-cyclo-but-3 -ene-1,2-dione were obtained as a yellow solid. Yield = 74%
Step 4:
(-) - 344-Chloro-2-hydroxy-3- (4-methyl-piperazine-1-sulfony1) -phenylamino] -4-1 [(5-methyl-furan-2-y1) - (tetrahydro-thiophen-2-y1) -méthylFaminol-cyclobut-3-ene-1,2 dione A mixture of 280 mg (1.4 mmol, 1.2 eq) of (-) - C- (5-methyl-furan-2-yl) -C-(tetrahydro-thiophen-2-yl) -methylamine (enantiomer 1, prepared in EXAMPLE 10, step 1) and 500 mg (1.16 mmol, 1 eq) of 3- [4-chloro-2-hydroxy-3- (4-methyl-piperazine) -1-sulfony1) -phenylamino] -4-ethoxy-cyclobut-3-ene-1,2-dione in 20 mL of methanol was heated to 50 C for 20 hours. The methanol was evaporated and the residue was taken up with some WO 2013/061004

60 dichloromethane and washed with an aqueous solution of dihydrogenphosphate sodium 1M.
The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. The residue was chromatographed on silica gel eluted with dichloromethane / methanol (98/2).
410 mg of 3-[4-chloro-2-hydroxy-3- (4-methyl-piperazin-1-sulfonyl) -phenylamino] -4- {
[(5-methyl furan 2-yl) - (tetrahydro-thiophen-2-yl) -methyl] amino-cyclo-but-3-ene-1,2-dione were obtained in the form of a bright yellow solid. Yield = 61%.
1 H NMR (DMSO-d 6, 400 MHz): 1.81-1.85 (m, 1H); 1.90-1.93 (m, 1H); 1.99-2.09 (m, 2H);
2.26 (s, 3H); 2.41 (s, 3H); 2.68 (se, 4H); 2.74-2.84 (m, 2H); 3.36 (se, 4H) ; 3.83-3.88 (m, 1H); 5.19 (t, j = 9.6 Hz, 1H); 6.06 (m, 1H); 6.29 (m, 1H); 6.80 (se, 1H);
7.90 (d, j = 8.6 Hz, 1H); 8.91 (d, j = 9.6 Hz, 1H); 9.48 (s, 1H); 10.00 (se, 1H).
BIOLOGICAL TESTS
EXAMPLE 23 In Vitro Affinity In Vitro affinity of the compounds of the present invention for receptors CXCR1 and CXCR2 was determined on a recruitment-type functional test of 13-arrestine after activation of the receiver.
CXCL8 activation of the CXCR2 receptor has been shown to be cells of the Pathilunter line flEK293-CXCR2 or CXCRI receptor in the cells of the line U2OS h CXCR1 13-arrestin leads to the recruitment of P-arrestine (Richardson, RM, RJ
Marjoram, LS Barak, R. Snyderman. 2003. Role of the cytoplasmic tails of CXCR1 and CXCR2 in mediating leukocyte migration, activation, and regulation. J.
Immunol. 170:
2904.-2911.) To evaluate the direct interaction of the CXCR2 or CXCR1 receptor with the P-Arrestine 2, a P-arrestin 2 recruitment test for CXCR2 or CX (R1 based on the Complementation of the enzyme f3-galactosidase (Oison KR, Eglen RM, Beta galactosidase complementation:
luminescent based assay platform for drug discovery. Assay Drug Dey Technol.
2007 Feb;
5 (1); 137-44,), as established by DiscoveRx Corporation was used. The stimulation of these two cell lines with CAUS (10 nM) induced recruitment of P-arrestine 2, as indicated by a significant increase in the induction factor. All the CXCR2 antagonists were tested in a dose-dependent manner and the concentration WO 2013/061004

61 corresponding to 50% inhibition of the response was determined (IC50 =
concentration of half inhibition).
Recruitment Test of the 13-arresti.In PathHunter Cells HEK293-CXCR2 or U2OS hCXCR1 P-arrestin (DiscoveRx Corporation) were seeded one night at 10 000 cells / well (384 format wells) in the middle of Opti MEM I.
preincubation with the antagonist or vehicle 30 min at 37 C and 5% CO2 was followed by 60 minutes stimulation with CXCL8 at 37 C and 5% CO2. The cells were then placed at room temperature for 30 minutes. The PathHunter detection reagent (DiscoverX
Corporation) has been added. After a 60 min incubation at temperature ambient, the 13-luminescence-induced galactosidase at 13-arrestin-interaction CXCR2 has been measured for 0.3 s in an Envision 2102 Multilabel Reader (PerkinElmer Life and Analytical Sciences). The data were analyzed by a procedure of nonlinear curve using the XLFit4 operating system (IDBS) and the IC50 were determined.
Compound CXCR1 CXCR2 N example (IC50; nM) (IC50; nM) (Enantiomer 2 of 244 53 diastereoisomer 2) (Diastereoisomer 1) (Diastereoisomer 2) WO 2013/061004

62 (Enantiomer 1 of 9999 * 9999 *
diastereoisomer 2) (Enantiomer 1 of 77 diastereoisomer 2) (diastereoisomer 2) (Enantiomer 2 of 692 56 diastereoisomer 1) (Enantiomer 2 of 1564 134 diastereoisomer 2) (diastereoisomer 1) WO 2013/061004

63 (Enantiomer 1 of 4554 273 diastereoisomer 1) 552,195 (Enantiomer 1) (Mixture 812 221 of enantiomers 1 and 2) (Enantiomer 2) WO 2013/061004

64 6,108 30 (diastereoisomer 2) (diastereoisomer 1) (diastereoisomer 2) 508,115 (diastereoisomer 1) (diastereoisomer 2) WO 2013/061004

65 580,153 (diastereoisomer 1) (diastereoisomer 1) 1096,272 (diastereoisomer 2) 12,483 83 WO 2013/061004

66 9999 * 1253 (diastereoisomer 2) 9999 * 9999 *
(diastereoisomer 1) 15,3808,294 16,652 23 17,384 44 WO 2013/061004

67 *: 9999 means not active EXAMPLE 24 Polypharmacology: receptor profiling Mesuredufkixcaiquesirçeffliles The experiments were carried out on the plateforrne FLIPR TETRA from Molecular Devices. After reading the basal level, the compounds have been added to cells expressing the chemokine receptor of interest and agonist activity has was read at 10 seconds. After an additional 10 minutes incubation, the cells have been activated, with a concentration equivalent to AC80, by an agonist of reference in order to detect if this compound has an antagonistic activity.
Each cell line expressing a chemokine receptor has been established based on Chem-1 cell stably expressing the recombinant form of the receptor to the WO 2013/061004

68 chemokines as well as an associated G protein, in order to couple the receiver to the way of calcium signaling.
21 receptors belonging to the chemokine receptor family (CCRs and CXCRs) have have been analyzed. All CXCR2 antagonists were tested in a dependent and concentration corresponding to 50% inhibition of the response was determined (IC50).
The compounds corresponding to the general formula (I) as well as the compound of Schering SCH-527123 were profiled on a panel of 20 chemokine receptors. he spring of this profiling that the compounds corresponding to the general formula (I) exhibit a polypharmacy. For example, the compound of Example 1 (Enantiomer 2 of diastereoisomer 2) inhibits the CCR4, CCR6, CCR7 and CXCR3 receptors with values IC50 respective of 410nM, 2.0nM, 8.71.IM and 1.3nM. The compound of the example (diastereoisomer 2) inhibits the CCR4, CCR6, CCR7, CCR8, CXCR3 and RPF1 with respective IC50s of 52nM, 4.4nM, 1.5tM, 620nM, 1.71.IM and 6.51.IM.
The Schering compound SCH-527123 was inactive or very little active on all of these receptors. It was also extremely interesting to note the strong activity of the compound of Example 1 (Enantiomer 2 of diastereoisomer 2) and the compound of Example 2 (diastereoisomer 2) on CXCR3 and CCR6.
IC50 (nM) CCR4 CCR6 CXCR3 Antagonist Example 1 410 2.0 1.3 (Enantiomer 2 of diastereoisomer 2) Example 2 52 8 1700 (diastereoisomer 2) Example 1 ND 2.2 55 (diastereoisomer 2) Example 2 250 6 216 (Enantiomer 1 of diastereoisomer 2) Example 6 ND 9.7 140 Example 10 39 1.6 93 Example 18 97 60 450 Example 19 8.1 11 510 Example 20 7.2 8.8 180 Example 22 9.4 2.2 150 ND: Not Determined WO 2013/061004

69 EXAMPLE 25 Dissociation constant The determination of the half-dissociation constants of the antagonists CXCR2 a been based on the In Vitro recruiting model of the I3-Arrestin previously described:
cell PathHunter HEK293-CXCR2 (DiscoveRx Corporation) were seeded one night to 20 000 cells / well (in 96-well format) in 100 L / well of culture medium OptiMEM-1%
FCS. Preincubation with the antagonist or the vehicle was performed for 1 hour to 37 C-5% CO2. The cells were then washed 3 times with 100 L / well of middle OptiMEM-1% SVF then a variable incubation (Oh-0.5h-6h-12h-24h) of the cells at 37 C-5% CO2 has been achieved. The cells were then stimulated with 4nM of CXCL8 at 37 C-5%
CO2 for 1h30. PathHunter Detection Reagent (DiscoveRx Corporation) has been added to reason of 50 L / well. After incubation for 60 minutes at room temperature ambient, the emitted luminescence, by the hydrolysis of the substrate by 13-galactosidase complemented when 13-Arrestin-CXCR2 interaction, was measured for 0.3 seconds / well with an Envision Multilabel Reader (PerkinElmer Life and Analytical Sciences). The data been analyzed by a non linear curve procedure using the [ogiciet el'exp] oitation XLFit4 (IDBS) and the 1050s were determined. The half-dissociation time has been determined on a regression of type y = (A * (1-exp (((- 1) * B) * x))) (where x = time and y = luminescence standardized) saturating concentration in antagonist.
Results: The molecules described in the examples of the invention were compared to the SCH-527123 molecule (described to have a pseudo-irreversible dissociation) (Pharmacological Characterization of SCH-527123, a Potent Allosteric Antagonist. JPET 322: 477-485, 2007).

WO 2013/061004

70 EXAMPLE 26 A / Metabolic Stabilities in Liver Microsomes Hepatic microsomes (Becton Dickinson) were incubated at a concentration of protein of 0.5 mg / mL in the reaction medium.
The reaction medium of the microsomes was composed of phosphate buffer pH:
7.4 to 100 mM, 100 mM MgCl2. (50/50), an ATP generation system consisting of a mixture of Nicotinamide Adenine Di-Phosphate (NADP), Glucose-6-Phosphate (G6P) to 1 mg / mL and Glucose-6-Phosphate Dehydrogenase (G6PDH) at 4 U / mL. Compounds have have been tested at 1 ILLM (DMSO 0.1%) Incubation medium samples after addition of microsomes were made to time 5, 10, 15, 30 and 60 minutes. At each time, the metabolic reaction has been stopped by addition of methanol (1 volume of medium incubation / 3 volumes of methanol). The disappearance of parent product was measured by LC / MS / MS analysis. The time for which 50% of product parent disappeared (T1 / 2) was calculated from the kinetics of disappearance of the parent product in function of time.
Antagonist Half-life time (min) SCH-527123 Stable (> 60min) Example 2 (diastereoisomer 2) 11 Example 1 27 (diastereoisomer 2) Example 2 9 (diastereoisomer 1) Example 3 (couple 3 of enantiomers 1 and 2) Example 6 Example 10 8 Example 18 Example 19 8 Example 20 17 Example 22 7 B / Metabolic Stabilities in Hepatocytes.

WO 2013/061004

71 Human hepatocytes were provided by Biopredic in a 24-well plate.
After 48 hours in culture, the hepatocytes were placed in a treatment containing 0.1% Serum Albumin Bovine and the compounds were tested at 1 ILLM (DMSO from 0.1%) Samples of incubation medium after addition of the test compound were been made to time t = 0, 1, 2, 4, 6 and 24 hours.
At each time, the metabolic reaction was stopped by adding methanol (1 volume medium incubation / 3 volumes of methanol). The disappearance of the parent product been measured by LC / MS / MS analysis. The time for which 50% (T1 / 2) of parent product has disappeared has been calculated from the kinetics of disappearance of the parent product based time.
Antagonist Half-life time (min) Example 1 (Enantiomer 2 of the 300 diastereoisomer 2) Example 1 539 (diastereoisomer 2) Example 2 (diastereoisomer 1) Example 2 (Enantiomer 2 of 229 diastereoisomer 2) Example 3 (Couple 141 of enantiomers 1 and 2) Example 2 (enantiomer 1 of diastereoisomer 2) Example 10 Example 18 82 Example 19 214 Example 20 211 Example 22 49

Claims (22)

1.
Di-substituted 3,4-diamino-cyclobutene-3-1,2-dione compound corresponding to the following general formula (I) or a pharmaceutically acceptable salt or solvate thereof acceptable:
in which, R1 represents a hydrogen atom or a methyl, R2 represents a five-membered ring selected from structures (1), (2), (3) and (4) following:
in which R5, R7a, X and X 'have the meaning given below, R3 represents an aromatic or heteroaromatic ring selected in the group formed by the cycles corresponding to the following formulas (a) to (o):

in which R7, R7a, Y and Z have the meaning given below, being specified that cycles (a) to (o) may possibly carry more than one R7 group, identical or different, the total number of such groups R7 being at most equal to the number of atoms substitutable cycle;
R4 represents an aromatic or heteroaromatic ring selected in the group formed by the cycles corresponding to the following formulas (p) to (z) and (aa) to (ak):

in which R7, R8, R9, R10, R11, R12, R13, R14 and R15 have the meaning given above after, R5 represents a hydrogen atom, a fluorine atom, an alkyl radical having from 1 to 5 carbon atoms or a fluorinated or perfluorinated alkyl radical having from 1 to 5 atoms of carbons, R6 represents a hydrogen atom, a -COOtBu radical or a -COOBn radical, R7 represents a halogen, a radical -R16, -CF3, -COR16, -OR16, -NR16R17, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -CONR16R17, -NR16CO2R17 or -CO2R16, R7a represents a hydrogen atom or an alkyl radical having from 1 to 5 atoms of carbons, R8 represents a hydrogen atom, a halogen atom, a radical -OH, a radical -SH, -CONHOR16, -CONR16OH, -NR16R17, -SO3H, -OCOR16, -NHSO2R16, -SO2NR16R17, -NHCOR16, -CONR16R17, -NR16CO2R17, -NHSO2NR16R17, -CO2R16, pyrrolyl, imidazolyl, triazolyl or tetrazolyl, R9, R10, R11 and R12 are the same or different and are independently chosen in the group consisting of hydrogen, a halogen atom, an alkyl radical, alkoxy, -CF3, -OCF3, -OH, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -CO2R16, or even when two of the radicals R9, R10, R11 and R12 are in ortho position on an aromatic or heteroaromatic ring selected from the group constituted by the cycles of formulas (p) to (z) and (aa) to (ak) above, then they can form together, with the bond that unites them, an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, R13 and R14 are the same or different and are independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl radical, CF3, -OCF3, -OH, -SH, -CN, -SO2R16, -SO2NR16R17, -NHSO2NR16R17, -NR16R17, -NR16CONR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -CO2R16, R15 represents a hydrogen atom, a radical -OH, -SO2R16, -COR16, -CO2R16, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R16 and R17 are the same or different and are independently selected from the group consisting of a hydrogen atom, an aryl radical, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, fluoroalkyl having 1 to 5 carbon atoms, cycloalkyl or cycloalkylalkyl, a CH2COOR18 group in which R18 represents an alkyl radical having from 1 to 5 atoms of carbon, or else when R16 and R17 are borne by the same nitrogen atom they form a heterocycle having between 3 and 7 links and possibly comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen in addition to the atom nitrogen by which they are carried, said heterocycle may be substituted by a group alkyl having 1 to 5 carbon atoms or a group ¨COOR18 in which R 18 represent an alkyl radical having 1 to 5 carbon atoms;
X and X ', identical or different, represent an oxygen atom, an atom of sulfur, or nitrogen atom substituted with an R 6 radical, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R15, and Z represents a carbon or nitrogen atom 2. Compound according to claim 1, characterized in that in formula (I) supra:
R1 represents a hydrogen atom, R2 represents a five-membered ring selected from structures (1), (2) and (3) following:
in which R5, R7a, X and X 'have the meaning given below, R3 represents an aromatic or heteroaromatic ring selected in the group formed by the cycles of the following formulas (a), (b) and (d):

in which R7, R7a, Y and Z have the meaning given below, being specified that cycles (a), (b) and (d) may optionally carry more than one R7 group, identical or different, the total number of such groups R7 being at most equal to the number atoms substitutable for the cycle;
R4 represents an aromatic or heteroaromatic ring selected in the group formed by the cycles corresponding to the formulas (p), (q), (t), (z), (ad), (ag) and (ah) following:
in which R8, R9, R10, R11, R12, R13 and R15 have the meaning given below, R5 represents a hydrogen atom, a fluorine atom, an alkyl radical having from 1 to 5 carbon atoms or a fluorinated or perfluorinated alkyl radical having from 1 to 5 atoms of carbons, R6 represents a hydrogen atom, a COOtBu radical or a COOBn radical, R7 represents a halogen, a radical R16, -CF3, -COR16, -OR16, -NR16R17, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -CONR16R17, -NR16CO2R17 or -CO2R16, R7a represents a hydrogen or an alkyl radical having from 1 to 5 carbon atoms carbons, R8 represents a hydrogen atom, a radical -OH, -SH, -CONHOR16, -CONR16OH, -NR16R17, -SO3H, -OCOR16, -NHSO2R16, -SO2NR16R17, -NHCOR16, -CONR16R17, -NR16CO2R17, -NHSO2NR16R17, -CO2R16, pyrrolyl, imidazolyl, triazolyl or tetrazolyl, R9, R10, R11 and R12 are the same or different and are independently chosen in the group consisting of a hydrogen atom, a halogen atom, a radical alkyl, alkoxy, -CF3, -OCF3, -OH, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -CO2R16, or even when two of the radicals R9, R10, R11 and R12 are in ortho position on an aromatic or heteroaromatic ring selected from the group constituted by the cycles corresponding to formulas (p), (q), (t), (z), (ad), (ag) and (ah) above, so they can to form together, with the bond which unites them, an aryl, heteroaryl ring, cycloalkyl or heterocycloalkyl, R13 is selected from the group consisting of a hydrogen atom, an atom halogen, a alkyl radical, -CF3, -OCF3, -OH, -SH, -CN, -SO2R16, -SO2NR16R17, -NHSO2NR16R17, -NR16R17, -NR16CONR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -CO2R16, R15 represents a hydrogen atom, a radical -OH, -SO2R16, -COR16, -CO2R16, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R16 and R17 are the same or different and are independently selected from the group consisting of a hydrogen atom, an aryl radical, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, fluoroalkyl having 1 to 5 carbon atoms, cycloalkyl or cycloalkylalkyl, a -CH2COOR18 group in which R18 represents an alkyl radical having from 1 to 5 atoms of carbon, or else when R16 and R17 are borne by the same nitrogen atom they form a heterocycle having between 3 and 7 links and possibly comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen in addition to the atom nitrogen by which they are carried, said heterocycle may be substituted by a group alkyl having 1 to 5 carbon atoms or a group -COOR18 in which R 18 represent an alkyl radical having 1 to 5 carbon atoms;
X and X ', identical or different, represent an oxygen atom, an atom of sulfur, or nitrogen atom substituted with an R 6 radical, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R15, and Z represents a carbon or nitrogen atom. 3. Compound according to claim 1 or 2, characterized in that in the formula (I) above:
R1 represents a hydrogen atom, R2 represents a ring with five atoms of structure (1) following:
in which R5 and X have the meaning given below, R3 represents a heteroaromatic ring corresponding to the following formula (d):

in which R7, Y and Z have the meaning given below, being specified that cycle (d) can possibly carry several R7 groups, identical or different, the total number of such R7 group being at most equal to the number of ring substitutable atoms ;
R4 represents an aromatic ring corresponding to the following formula (t):
in which R8, R9, R10, R11 and R12 have the meaning given below, R5 represents a hydrogen atom, a fluorine atom, an alkyl radical having from 1 to 5 carbon atoms or a fluorinated or perfluorinated alkyl radical having from 1 to 5 atoms of carbons, R6 represents a hydrogen atom, a COOtBu radical or a COOBn radical, R7 represents a halogen atom, a radical R16, -CF3, -COR16, -OR16, -NR16R17, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -CONR16R17, -NR16CO2R17 or -CO2R16, R8 represents a hydrogen atom, a radical -OH, -SH, -CONHOR16, -CONR16OH, -NR16R17, -SO3H, -OCOR16, -NHSO2R16, -SO2NR16R17, -NHCOR16, -CONR16R17, -NR16CO2R17, -NHSO2NR16R17, -CO2R16, pyrrolyl, imidazolyl, triazolyl or tetrazolyl, R9, R10, R11 and R12 are the same or different and are independently chosen in the group consisting of a hydrogen atom, a halogen atom, a radical alkyl, alkoxy, -CF3, -OCF3, -OH, -NO2, -CN, -SO2R16, -SO2NR16R17, -NR16COR17, -NR16CO2R17, -CONR16R17, -COR16 or -CO2R16, or even when two of the radicals R9, R10, R11 and R12 are in ortho position on the aromatic ring (t), they can form together, with the binding that brings them together, one aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring, R15 represents a hydrogen atom, a radical -OH, -SO2R16, -COR16, -CO2R16, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R16 and R17 are the same or different and are independently selected from the group consisting of a hydrogen atom, an aryl radical, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, fluoroalkyl having 1 to 5 carbon atoms, cycloalkyl or cycloalkylalkyl, a CH2COOR18 group in which R18 represents an alkyl radical having from 1 to 5 atoms of carbon, or else when R16 and R17 are borne by the same nitrogen atom they form a heterocycle having between 3 and 7 links and possibly comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen in addition to the atom nitrogen by which they are carried, said heterocycle may be substituted by a group alkyl having 1 to 5 carbon atoms or a group ¨COOR18 in which R 18 represent an alkyl radical having 1 to 5 carbon atoms;
X represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R6, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by a radical R15, and Z represents a carbon atom or a nitrogen atom. A pharmaceutical composition comprising an effective amount of a compound or a salt pharmaceutically acceptable form of said compound according to claim 1 in association with a pharmaceutically acceptable solvent or carrier. 5. Compound according to claim 1 or pharmaceutical composition according to claim 4 for its use as a medicine. 6. Compound according to claim 1 or pharmaceutical composition according to claim 4 for its use in the treatment of diseases mediated by .alpha.-chemokines. 7. The compound or pharmaceutical composition according to claim 6 for its use in the treatment of diseases of the group comprising neutrophilic dermatoses, especially psoriasis, atopic dermatitis, acne, rosacea, asthma, pulmonary diseases chronic obstructive diseases, adult respiratory diseases, arthritis, diseases Inflammatory bowel disease, Crohn's disease, transplant rejection, cystic fibrosis and skin cancers. 8. Compound or pharmaceutical composition according to claim 6 for its use in the treatment of dermatological diseases such as dermatitis neutrophilic, including psoriasis, atopic dermatitis, acne and rosacea. 9. The compound of claim 1 selected from the list comprising:
1 / - 2-hydroxy-N, N-dimethyl-3 - (2 - methyl [(5-methylfuran-2-yl) - (2-methyl)]
tetrahydrofuran-2-yl) -methyl] amino} -3,4-dioxo-cyclobut-1-enylamino) -benzamide hydroxy-N, N-dimethyl-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2 yl) -methyl] amino} -3,4-dioxo-cyclo-but-1-enylamino) -benzamide 3 / - (S) -1 - [2-fluoro-3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate methyl 4 / - (S) -1 - [2-fluoro -3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl)}
methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate isopropyl 5 / - (S) -1 - [2-fluoro -3 - (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl)}
methyl] -amino} -3, 4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate ethyl 6 / - (R) -1- [2-hydroxy-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate methyl 7 / - (S) -1- [2-hydroxy-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate methyl hydroxy-N-methyl-3- (2 - {[(S) - (5-methyl-furan-2-yl) -tetrahydro-thiophen-2-yl) methyl] -amino} -3,4-dioxo-cyclo-but-1-enylamino) -N- (2,2,2-trifluoro-ethyl) -benzamide 9 / - {[2-hydroxy-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -3,4-methyl dioxo-cyclobut-1-enylamino) -benzoyl] -methyl-amino} -acetate 10β-Chloro-2-hydroxy-N, N-dimethyl-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzenesulfonamide 11 / - 2-hydroxy-N, N-dimethyl-3- (2 - {[(R) - (5-methyl-furan-2-yl) -tetrahydro-furan-2-yl) methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzamide 12 / - 2-hydroxy-N, N-dimethyl-3- (2 - {[(S) - (5-methyl-furan-2-yl) -tetrahydro-furan-2-yl-methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzamide) 13β- (3,4-dioxo-2 - {[phenyl- (tetrahydrofuran-2-yl) -methyl] -amino} -cyclobut-1-enyl-amino) -2-hydroxy-N, N-dimethyl-benzamide 14 - - 3- (2 - {[((R) -2,2-dimethyl- [1,3] dioxolan-4-yl) - (5-methyl-furan-2-yl) -methyl] -amino} -3, 4-dioxo-cyclobut-1-enylamino) -2-hydroxy-N, N-dimethyl-benzamide 15 ((S) -1- [2-Fluoro-3- (2 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -Methyl 3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2-carboxylate 16 / 3-(2-hydroxy-pyridin-3-ylamino) -4 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen) 2-yl) -methyl] -amino} -cyclobut-3-ene-1,2-dione 17β-N - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -4-(1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino) -cyclobut-3-ene-1,2-dione 18 / (-) -2-hydroxy-N-methyl-3- (2 - {[(S) - (5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] amino} -3,4-dioxo-cyclobut-1-enylamino) -N- (2,2,2-trifluoroethyl) benzamide 19 / (-) -{[2-hydroxy-3- (2 - {[(S) - (5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -methyl-amino} -acetate methyl 20 / (-) -1- [2-hydroxy-3- (2 - {[((S) -5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) -benzoyl] -pyrrolidine-2- (R) -carboxylate methyl 21 / (-) -6-chloro-2-hydroxy-N, N-dimethyl-3- (2 - {[((S) -5-methyl-furan-2-yl) - (tetrahydro) thiophen-2-yl) -methyl] -amino} -3,4-dioxo-cyclobut-1-enylamino) benzamide 22 / (-) - 3- [4-Chloro-2-hydroxy-3- (4-methyl-piperazin-1-sulfonyl) -phenylamino] -4 - {[(5-methyl-furan-2-yl) - (tetrahydro-thiophen-2-yl) -methyl] -amino} -cyclobut-3-ene 1,2-dione